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Journal of Complementary and Integrative Medicine

Editor-in-Chief: Lui, Edmund

Ed. by Ko, Robert / Leung, Kelvin Sze-Yin / Saunders, Paul / Suntres, PH. D., Zacharias

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A review of Tunisian medicinal plants with anticancer activity

Wissem Aidi Wannes
  • Corresponding author
  • Laboratory of Aromatic and Medicinal Plants, Biotechnologic Center Borj-Cedria Technopark, Hammam-Lif, Tunisia
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Moufida Saidani Tounsi
  • Laboratory of Aromatic and Medicinal Plants, Biotechnologic Center Borj-Cedria Technopark, Hammam-Lif, Tunisia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Brahim Marzouk
  • Laboratory of Aromatic and Medicinal Plants, Biotechnologic Center Borj-Cedria Technopark, Hammam-Lif, Tunisia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2017-09-13 | DOI: https://doi.org/10.1515/jcim-2017-0052


Cancer is a major public health problem in the world. The use of the medicinal plants in cancer prevention and management is frequent in Africa, especially in Tunisia, and it is transmitted from generation to generation within cultures. Many previous studies showed that a wide range of Tunisian medicinal plants exerted cytotoxic and anticancer activity. A comprehensive review was conducted to collect information from scientific journal articles, including indigenous knowledge researches, about Tunisian medicinal plants used for the prevention and management of cancer. The aim of this review article is to provide the reader with information concerning the importance of Tunisian medicinal plants in the prevention and management of cancer and to open the door for the health professionals and scientists working in the field of pharmacology and therapeutics to produce new drug formulations to treat different types of cancer.

Keywords: anticancer potential; cancer; cytotoxicity; medicinal plants; Tunisia


Living in harmony with the nature, all human societies have used plants not only as sources of nutrition but also as therapy against diseases. Plants have formed the basis of refined traditional medicine systems which have been in existence for thousands of years and continue to provide mankind with new remedies. Natural products and their derivatives represent more than 50 % of all drugs in clinical used in the world. It is also a fact that one quarter of all medicinal prescriptions are formulations based on substances resulting from plants or plant-derived synthetic analogs [1].

The World Health Organization [2] estimated that 80 % of the inhabitants of the earth choose traditional medicine for primary health needs. In developed countries, the raw materials for manufacturing essential drugs are extracted from medicinal plants, harnessing its natural properties of healing. In many developing countries, traditional medicine is still the mainstay of healthcare and most of the drugs and cures come from plants [3]. From 250,000 to 500,000 plants in the worldwide, a small percentage has been examined for its medicinal properties. The National Cancer Institute has examined more than 30,000 plants with anticancer activity [4]. Tunisia, located on the shores of the Mediterranean, is a rich repository of various plant resources. It has more than 500 species of medicinal and aromatic plants, and a total of 2,163 varieties; the majority of these plants are found in harsh environments such as arid and semiarid conditions [5]. Many of Tunisian medicinal plants have been experimentally validated to treat several illness especially diabetes, ulcer, cancer, hypertension and hyperlipidemia. Nonetheless, there is still a dearth of updated comprehensive compilation of promising medicinal plants from Tunisia for each illness. Only one study was found to define 19 Tunisian medicinal plants that have been experimentally tested and shown to be of some value in diabetes [6]. In the present research 70 medicinal plants were studied for their anticancer and cytotoxic activities. The World Health Organization [2] has mentioned that cancer is increasingly growing as a major health problem in both developed and developing countries among the chronic diseases. Cancer imposes a heavy economic, health and social burden. It is a global pandemic affecting both developed and developing regions, but the cancer toll is rapidly increasing in low- and middle-income countries, where resources for prevention, diagnosis and treatment are limited or nonexistent [7]. In worldwide, cancer incidence could potentially increase to as many as 17 million new cases per year by 2020. Of these, it is estimated that as many as 1.5 million cases will occur alone in Africa [8]. With 10,000 new cases each year, this small country Tunisia also is on a rising cancer curve [9].

According to the National Cancer Institute [10], there are more than 100 types of cancer. Most cancers are named for where they start such as breast cancer starts in the breast, lung cancer starts in the lung and ovarian cancer starts in ovaries. Cancer begins inside a cell, the basic building block of all living things. Normally, when the body needs more cells, older ones die off and younger cells divide to form new cells that take their place. When cancer develops, however, the orderly process of producing new cells breaks down. Cells continue to divide when new cells are not needed, and a growth or extra mass of cells called a tumor is formed. Over time, changes may take place in tumor cells that cause them to invade and interfere with the function of normal tissues. Cancer cells can invade nearby tissues and can spread through the bloodstream and lymphatic system to other parts of the body. The major problem of cancer treatment is the adverse effects of chemotherapy drugs which have been reported to have negative impact in our body and also suppression of the immune system. Besides, the effectiveness of chemotherapy is limited by drug resistance [11].

There is an urgent need for new anti-cancer drugs and therapies. Plant-derived natural compounds have been in use against various ailments since ancient period and has been regarded as promising drugs against cancer without much of side-effects. In this war against cancer, the role of alternative medicine has become more and more important. Throughout the world, scientists are discovering from old medicinal plants new properties that hold great promises for cancer prevention and treatment [12]. In the same way, several plant derived drugs were approved last decades. Alkaloids, such as vinblastine isolated from Catharanthus roseus, is commonly used to treat Hodgkin’s lymphoma [13]. Camptothecin, another monoterpene indole alkaloid isolated from certain angiosperms, has been effective against recurrent colon cancer and its cellular target is DNA topoisomerase I [14]. Paclitaxel, a diterpene alkaloid isolated from Taxus brevifolia is effective against breast and ovarian cancer and acts by blocking depolymerization of microtubules [15]. Thus, plants may play an important role in drug development programs. Several plants have been traditionally recommended for prevention and treatment of cancer and the role of these plants in the management of cancer in vitro and/or in vivo conditions have been determined by many researchers. Hence, the present review defines Tunisian medicinal plants that have been experimentally tested against cancer cells and shown to have cytotoxic activity.


The search was done in electronic databases of PubMed, Scopus, ScienceDirect and Google Scholar for studies using the key terms: anticancer potential, cancer, cytotoxicity, medicinal plants and Tunisia. The references list included all articles related to the subject and published from 1997 to 2017. All plant species were taxonomically validated; the Latin scientific name and family were confirmed using The Plant List site (http://www.theplantlist.org/).

Findings and discussion

From the findings, 70 medicinal plants in Tunisia with studies conducted on their anticancer and cytotoxicity activities were reported (Table 1). In Tunisia, lung cancer has been the most prevalent cancer for men and breast cancer for women [16]. However, most studies have addressed colon cancer as mentioned in Table 2 and Figure 1. Several plant compounds have been reported to be probably responsible for anticancer effects. Additionally, some compounds were isolated from the plants and the effects of these compounds on various cell lines were studied (Table 3). Phenolic and terpene compounds were the most highlighted to have anticancer effects on various cancers in most studies. As shown in Table 1, these compounds specifically intervene by inhibiting growth proliferation and destruction of tumor cells only by affecting cancer cells. In addition, most of medicinal plants with anticancer activity have antioxidant activity due to phenolic and terpene compounds. Therefore, these plants may, at least in part, exert their anticancer effects by counteracting free radicals.

Distribution of Tunisian medicinal plants according to different cancer types.
Figure 1:

Distribution of Tunisian medicinal plants according to different cancer types.

Table 1:

Anticancer effects of Tunisian medicinal plants.

Table 2:

Effect of Tunisian medicinal plants on different cancers.

Table 3:

Anticancer effect of new compound isolated from Tunisian medicinal plants.

Acacia cyclops Mill. (Fabaceae)

A phytochemical investigation of A. cyclops pods led to the isolation of two new monoterpenoid glycosides, namely cyclopside 1 and cyclopside 2. The in vitro cytotoxic effect of these two compounds was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against the human breast cancer (MCF-7) and ovarian cancer (OVAR) cell lines. Results showed that the highest cytotoxic activity was exhibited by the cyclopside 1 against MCF-7 cell line with an inhibition percentage of 90.88 % at the concentration of 50 µg/mL [17].

Acacia salicina Lindl. (Fabaceae)

The cytotoxicity effect of aqueous, methanol, ethyl acetate and total oligomer flavonoid extracts from A. salicina leaf was investigated against human chronic myelogenous leukemia (K562) and leukemia murine (L1210) cell lines. A pronounced cytotoxic effect on both leukemia cell lines was detected in total oligomer flavonoid, methanolic and ethyl acetate extracts of A. salicina leaf [18]. The cytotoxic activity exhibited by A. salicina leaf depended on its chemical composition. Flavonol 3-O-glycosides (isorhamnetin 3-O-neohesperidoside), isolated from A. salicina leaf, had protected the cells against oxidative stress by inhibiting xanthine oxidase and superoxide anion scavengers [109]. As an antioxidant biomarker, rutin (quercetin-3-rutinoside), a flavonol glycoside, had been recently quantified in A. salicina leaf (10.42 µg/mg) using RP-HPTLC method [110]. Or, rutin has been extensively studied for anticancer effects. In fact, rutin caused a significant reduction in tumor size of human leukemia (HL-60) cells implanted in a murine model [111]. Rutin is also known to inhibit cancer cell growth by cell cycle arrest and/or apoptosis, along with inhibition of proliferation, angiogenesis and/or metastasis in colorectal cell lines [112].

Achillea cretica L. (Asteraceae)

Four sesquiterpene-lactone compounds, isolated from the aerial parts of A. cretica, were examinated for their in vitro cytotoxic activity against the human colon cancer (HCT-116 and IGROV-1), ovarian cancer (OVCAR-3) and breast cancer (MCF-7) cell lines using MTT assay. Results showed that only one compound, namely the chlorinated sesquiterpene lactone, presented a modest activity against the four human cell lines when compared to the controls (doxorubicin and tamoxifen). However, the two new epimeric secoguaianolides of tanaphallin and the known vomifoliol were less active [19].

Allium roseum L. (Alliacea)

The cytotoxicity activity of essential oil from A. roseum bulb against two human colonic adenocarcinoma (HT29 and CaCo2) cell lines was investigated by Touihri et al. [20]. They indicated that A. roseum bulb essential oil provided interesting antiproliferative activity was investigated against both HT29 with IC50=4.64 µg/mL and CaCo2 with IC50=8.22 µg/mL. They mentioned that this potential antiproliferative effect appears to be related mainly to the presence of organosulfur compounds, mainly methyl methanethiosulfate (8.91 %), 3-vinyl-1,2-dithiacyclohexa-5-ene (6.81 %), diallyl trisulfide (6.76 %), disulfide, methyl (methylthio) methyl (4.57 %), methyl 2 propenyl disulfide (3.6 %), 3-vinyl-1,2-dithiacyclohex-4-ene (3.56 %) and diallyl disulfide (3.16 %). Among these organosulfur compounds, methyl methanethiosulfate isolated from A. tuberosum had inhibited in vitro proliferation of human breast cancer (MCF-7) cell line. This compound had also in vivo antitumor activity in sarcoma-180 tumor-bearing-mice [113]. Allyl sulfides isolated from A. sativum bulb essential oil showed various effects on inhibition of proliferation of human liver tumor (J5) cell. Diallyl disulfide markedly suppressed the growth of cultured human colon tumor (HCT-15) cell line [101].

Allium sativum L. (Alliacea)

Manganese superoxide dismustase, a metalloenzyme isolated and purified from A. sativum bulb, was evaluated for in vitro antitumor activity against two tumor cell lines: porcine endothelial (PAE) and mouse melanoma (B16F0). The treatment of both tumoral cell lines with 8 Units of manganese superoxide dismutase for 3 days was able to modify the intracellular level of reactive oxygen species by eliminating superoxide anion and producing hydrogen peroxide. The cell viability of the two lines exposed to manganese superoxide dismustase was not significantly affected but the cell multiplication was arrested. This effect obtained in the presence of manganese superoxide dismutase correlated with the activation and modulation of phospho-extracellular signal-regulated kinases proteins, implicated in the control of several biological processes including cell proliferation [21].

Artemisia campestris L. (Asteraceae)

The hexane, water and ethanol/water extracts of A. campestris aerial part as well as its essential oil were evaluated for their antitumor growth inhibition of human colon cancer (HT-29) cells using the MTT test. The essential oil, infusion and ethanol/water extract of A. campestris tested at maximum concentration (100 µg/mL) and exhibited a significant antitumor activity against the HT-29 cells with 19.5 %, 59.5 % and 88.7 %, respectively. However, no activity was shown by the hexane extract of this plant at any concentration. A. campestris essential oil contained high concentration of β-pinene, α-pinene, germacrene D, myrcene and limonene terpenes [22]. The terpenes have been described by their antitumor activity against several types of cancers such as breast, liver, skin and pancreatic cancers [114]. In other hand, Akrout et al. [22] attributed the activity of both ethanol/water and infusion extracts of A. campestris to their antioxidant activity (DPPH: IC50=2.05 and 0.65 mg/mL, respectively) as well as their polyphenol (463.3 and 311.5 mg gallic acid equivalent/g extract, respectively) and flavonoid (56.3 and 24.0 mg rutin equivalent/g extract, respectively) contents. The correlation between the inhibition of cancer cell proliferation and the levels of polyphenols and flavonoids, along with the correlation between antitumor and antioxidant activities, has been reported in previous studies [115, 116, 117].

Artemisia herba-alba Asso. (Compositae)

The leaf extract of A. herba-alba had a high anticancer activity against three human tumor cell lines with IC50=81.59 mg/L for human bladder carcinoma (RT112) cells, IC50=59.05 mg/L for human laryngeal carcinoma (Hep2) cells and IC50=90.96 mg/L for human myelogenous leukemia (K562) cells [23]. The phenolic compounds detected in Tunisian A. herba-alba were chlorogenic acid, chlorogenic acid isomers, apigenin derivatives and quercetin derivative [118]. Among these bioactive phenolic compounds, administration of the flavonoids quercetin and apigenin in syngeneic mice had inhibited growth and metastatic potential of melanoma (B16-BL6) cells along with significant decrease in their invasion in vitro [119]. Belkaid et al. [120] had reported that the chemopreventative properties of chlorogenic acid which revealed a potential new role for microsomal glucose-6-phosphate translocase in brain tumor progression.

Astragalus gombiformis Pomel (Fabaceae)

The dichloromethane, methanol and petroleum ether extracts of A. gombiformis leaf as well as its alkaloids were evaluated for their cytotoxicity activity against human lung epithelial carcinoma (A549) cell line using the colorimetric MTT assay. The leaf of A. gombiformis was biologically active and showed a high cytotoxic effect. In particular, the leaf dichloromethane extract of A. gombiformis exhibited the highest cytotoxic activity with an IC50 of 85 µg/mL after 48 h of incubation [24]. The cytotoxicity activity of A. gombiformis leaf extract can be related to swainsonine and its derivatives, which are widely distributed in Astragalus species [121] and the antitumoral efficient of swainsonine was proven by Sun et al. [122].

Capparis spinosa L. (Capparidaceae)

The cytotoxicity activity of hydroethanolic extract from C. spinosa leaf against human epithelial cervical cancer (HeLa) cell line was investigated using the MTT assay. Results showed that C. spinosa extract had an efficient cytotoxic effect with IC50=1.14 µg/mL. The hydroethanolic extract of C. spinosa leaf contained a considerable amount of polyphenol, flavonoid and anthocyanin compounds which contributed at significant anticancer activity [25]. In other study, Yu et al. [123] had reported that the total alkaloids of C. spinosa can inhibit the growth of human gastric adenoma (SGC-790) cells. Additionally, the lectin isolated from C. spinosa seed inhibited the proliferation of both HepG2 and MCF-7 cell lines [124].

Carpobrotus edulis L. (Mesembryanthemaceae)

The cytotoxic effect of aqueous and aqueous ethanol extracts from C. edulis against human colon cancer (HCT-116) cell line was determined using the MTT assay. The ethanol-water extract of C. edulis exhibited a cytotoxic effect against HCT116, with a significant decrease in cell viability after 24 h of incubation. Phenolic composition analysis indicated the presence of seven bioactive compounds divided in three phenolic acids (sinapic, ferulic and ellagic acids) and four flavonoids (luteolin7-o-glucoside, hyperoside, isoquercitrin and isorhamnetin 3-O-rutinoside) which are known as bioactive metabolites and could play an important role against anticancer activity [26].

Ceratonia siliqua L. (Fabaceae)

The essential oil of carob (C. siliqua) pods was investigated for its cytotoxicity activity against human cervical cancer (HeLa) and breast cancer (MCF-7) cell lines using the MTT assay. The essential oil of C. siliqua pods had growth inhibition effect on tumoral human cells in a dose-dependent manner. The inhibition on the considered cell lines was significantly stronger in HeLa with IC50 of 210 μg/mL compared to 800 μg/mL for MCF-7. It was also noticed that the essential oil of C. siliqua pods exhibited lower toxicity to non-cancerous human cell and had potential selectivity cancer cell lines [106]. Additionally, Dhaouadi et al. [125] had determined the cytotoxicity effect of the aqueous-acetone extract from traditionally derived carob pod-pulp syrup against human tumorigenic neuroblastoma (SH-SY5Y), non-tumorigenic (3T3) fibroblast and mouse embryonic stem cells (D3) using the MTT assay. They noticed that carob syrup extracts reduced tumoral human cell viability in a dose-dependent manner with IC50=311.7 µg/mL for tumorigenic SH-SY5Y cells, IC50=586.28 µg/mL for non-tumorigenic 3T3 and IC50=476.81 µg/mL for non-tumorigenic embryonic mouse stem cells (D3). It was also clear that carob syrup exhibited low toxicity to non-cancerous cell in comparison to tumorigenic cell lines and it had potential selectivity to cancer cell lines. Recently, Sassi et al. [27] had evaluated the antiproliferative activity of aqueous extract and total oligomer flavonoids from C. siliqua leaf against murine leukemia cell line (L1210) using the MTT assay. Results showed that the increasing doses of aqueous extract and total oligomer flavonoids induced a dose-dependent cytotoxic effect with an IC50 of 65 µg/mL for total oligomer flavonoids and 140 µg/mL for aqueous extracts. Sassi et al. [27] found a positive correlation between the total phenolic content of aqueous extract, and its cytotoxicity toward L1210 cells (r2=0.917).

Cistus monspeliensis L. (Cistaceae)

The in vitro cytotoxic activity of hexanoic extract from C. monspeliensis leaves against murine monocyte/macrophages (J774A1), human melanoma (A375) and human breast cancer (MCF7) cell lines was determined by the calorimetric MTT assay. A pronounced growth inhibition was showed against A375 cell line, with an IC50 value of 82.42 mg/mL at 24 h and 52.44 mg/mL at 72 h. Results indicated higher activity of hexanoic C. monspeliensis extract if compared to 6-mercaptopurine (IC50=142.36 mg/mL at 72 h) used as reference drug. C. monspeliensis could be capable to exert its antiproliferative activity by the appreciable presence of polyunsaturated fatty acids (especially α-linolenic acid), vitamin E and phenolics [28].

Citrullus colocynthis L. (Cucurbitaceae)

Two new tetracyclic cucurbitane-type triterpene glycosides (acetyl glucocucurbitacin E and coumaroyl-acetyl glucocucurbitacin I) were isolated from an ethyl acetate extract of Citrullus colocynthis leaves together with four known cucurbitacins (cucurbitacin E, glucocucurbitacin E, cucurbitacin I and glucocucurbitacin I). Evaluation of the in vitro cytotoxic activity of the isolated compounds against two human colon cancer (HT29 and Caco-2) cell lines and one normal rat intestine epithelial (IEC6) cell line revealed that one of the isolated compounds, coumaroyl-acetyl glucocucurbitacin I, presented interesting specific cytotoxic activity at 1 μg/mL toward colorectal cell lines but not for non-cancerous IEC6 cells [29]. In earlier study, cucurbitacin I compound had been previously shown to have cytotoxic activity against SW480 [126] and Colo205 [127] colorectal cancer cell lines.

Convolvulus althaeoides L. (Convolvulaceae)

The essential oil of C. althaeoides flower was tested for its cytotoxic activity toward the human breast cancer (MCF-7) cells using the MTT assay. This essential oil exerted a significant cytotoxic activity against the tested cell line (IC50=8.16 µg/mL). Cytotoxic activity of C. althaeoides flower may be attributed to its specific essential oil components [30]. Some compounds in the essential oil of C. althaeoides leaf had previously been tested for their cytotoxic properties, namely α-humulene, caryophyllene oxide, β-caryophyllene and germacrene D, against MCF-7, MDAMB-231, Hs 578T, PC-3 and Hep-G2 cell lines [128]. Cytotoxic activity of the C. althaeoides essential oil may be due to a synergistic effect of these active compounds [30].

Conyza canadensis L. (Asteraceae)

The cytotoxic activity of petroleum ether, ethyl acetate and methanol extracts of C. canadensis aerial part was investigated on Hep-2 using MTT assay. The most active extracts were found to be ethyl acetate (IC50=45 µg/mL) and petroleum ether (IC50=50 µg/mL) extracts [129]. According to the bioactivity-guided fractionation of the n-hexane and chloroform phases of the methanol extract from C. canadensis root, two new compounds: conyzapyranone A and conyzapyranone B, as well as 2 γ-lactone acetylene derivatives (4E,8Z-matricaria-γ-lactone and 4Z,8Z-matricaria-γ-lactone), triterpenes (epifriedelanol, friedeline, taraxerol and simiarenol), sterols (spinasterol and β-Sitosterol + stigmasterol), a hydroxy fatty acid (9,12,13-trihydroxy-10(E)-octadecenoic acid) and a flavonoid (apigenin) were isolated. Among these isolated compounds, conyzapyranones A and B, 4E,8Z-matricaria-γ-lactone, 4Z,8Z-matricaria-γ-lactone, Epifriedelanol, spinasterol and apigenin were found to have remarkable antiproliferative activity against cervical cancer (HeLa), breast cancer (MCF-7) and epidermoid carcinoma (A431) cell lines. It is better to mention that conyzapyranone B, 4E,8Z-matricaria-γ-lactone and spinasterol proved to be substantially more potent against these tumor cell lines than against non-cancerous human fetal fibroblast (MRC-5) cell line and can therefore be considered selective antiproliferative natural products [31]. In another study, erigeronol, a new triterpene derivative, was isolated from the ethanolic extract of C. canadensis aerial part as a potent cytotoxic compound with IC50=7.77 µg/mL on melanoma B16 cell line by the MTT method [107].

Cotula coronopifolia L. (Asteraceae)

Two natural compounds, namely 6-methoxy-1-benzofuran-4-ol and stigmast-22-ene-3-ol, have been isolated from C. coronopifolia aerial part. Cytotoxic activity of these two natural compounds against human cervical cancer (HeLa) cell line was tested using the MTT assay. The 6-methoxy-1-benzofuran-4-ol compound showed cytotoxicity against HeLa with IC50=14.17 μg/mL, whereas stigmast-22-ene-3-ol compound had an IC50=45.72 μg/mL [32].

Crataegus azarolus L. (Rosaceae)

The cytotoxicity of total oligomer flavonoid extract from C. azarolus leaf against mouse melanoma (B16F10) cells was determined using the MTT assay. As total oligomer flavonoid extract of C azarolus leaf showed a significant inhibiting growth effect against B16F10 both in vitro and in vivo. The chemical composition of total oligomer flavonoid extract from C. azarolus leaf was rich in chlorogenic acid, (−)-epicatechin, rutin, hyperoside, vitexin-2̋-O-rhamnoside, procyanidin B2, procyanidin C1, oleanolic acid and ursolic acid [33]. The antitumoral effect of total oligomer flavonoid extract from C. azarolus leaf might be ascribed to the presence of specific bioactive compounds in its composition. In fact, Mustapha et al. [33] had demonstrated in this work the effective inhibitory effect of (−)-epicatechin on murine melanoma cell proliferation. Belkaid et al. [120] had reported that the chemopreventative properties of chlorogenic acid which revealed a potential new role for microsomal glucose-6-phosphate translocase in brain tumor progression. Li et al. [130] had shown that the combination of quercetin and hyperoside (1:1 ratio) had anticancer effect on 786-O human renal cancer cells. Concerning the phenolic vitexin compound, it had affected cell growth and apoptosis of colon cancer cells [131] and it had induced apoptosis in human leukemia (U937) cells via a mitochondrial signaling pathway [132]. Procyanidins have also attracted attention due to their chemopreventive action and promising strategy to prevent cancer. Among procyanidins, Avelar and Gouvêa [133] had proven the cytotoxicity effect of procyanidin B2 against human breast adenocarcinoma (MCF-7) cells and Kin et al. [134] had mentioned that procyanidin C1 from Cinnamomi Cortex inhibited TGF-β-induced epithelial-to-mesenchymal transition in the human lung cancer (A549) cells. Araújo et al. [135] had reported that oleanolic acid decreased the metastasis of a melanoma (B16F10) model in vivo. Furthermore, ursolic acid, which is an isomer of oleanolic acid, significantly reduced angiogenesis in the B16F10 mouse melanoma model [136]. Another study carried out by Martínez Conesa et al. [137] had shown that rutin significantly reduced the number of pulmonary metastatic nodules induced by a subcutaneous injection of B16F10 cells.

Crataegus monogyna L. (Rosaceae)

The cytotoxicity effect of polyphenolic extract from C monogyna leaf, fruit peel, pulp and syrup in human colon adenocarcinoma (undifferentiated Caco-2) and non-tumorigenic intestinal epithelial (differentiated Caco-2) cells was determined using the MTT assay. Results showed that all extracts did not show any toxic effect on differentiated Caco-2 cells; while, they were found cytotoxic to cancer Caco-2 cells, except, extracts of pulp and syrup of C. monogyna [34]. Mraihi et al. [35] had also determined the cytotoxicity of ethanolic extract from C. monogyna fruit against human breast adenocarcinoma (MCF-7) cell line using the MTT assay. Results showed that C. monogyna fruit presented a very important effectiveness against MCF-7 with IC50=38.92 µg/mL. C. monogyna fruit was characterized by the presence of nine flavonoids glucosides, namely isoquercitin, quercitin digalactoside, quercitin diglucoside, quercitin-3-O-galactoside, kaempferol-3-galactoside, kaempferol-3-glucoside, luteolin-7-O-rutinoside, apigenin-7-O-glucoside, catechin and epicatechin. All these flavonoids were found to be active against different cancer types. So, quercitin had induced antiproliferative activity against human hepatocellular carcinoma (Hep G2) cells [138]. Kaempferol had anticancer effects on human pancreatic cancer Miapaca-2, Panc-1 and SNU-213 cells. In particular, kaempferol effectively inhibited the migratory activity of human pancreatic cancer cells at relatively low dosages without any toxicity [139]. Luteolin exhibited a stronger cytotoxic activity against human chronic myelogenous leukemia (K562) cells [40]. Manikandan et al. [140] had reported that catechin inhibited the growth of human colon adenocarcinoma (HCT 15 and HCT 116) and human larynx carcinoma (Hep2) cell lines. Mustapha et al. [33] had demonstrated the effective inhibitory effect of epicatechin on murine melanoma cell proliferation.

Crithmum maritimum L. (Apiaceae)

The in vitro cytotoxic activity of C. maritimum aerial part and root essential oils as well as the dillapiole fraction was evaluated against human lung epithelial carcinoma (A549) and human epithelial cervical cancer (HeLa) cell lines using the calorimetric MTT assay. Result showed that the dillapiole fraction presented the best cytotoxic effect against HeLa cell lines with IC50=12.02 μg/mL but a moderate activity against the A549 with IC50=228.44 μg/mL which can be explained by the selectivity phenomenon of dillapiole against the cancer cell lines. C. maritimum aerial part essential oil exhibited a moderate activity with IC50=185.21 μg/mL for HeLa and 578.68 μg/mL for A549. Concerning C. maritimum root essential oil, it found to be the less active with IC50=1928.45 μg/mL for HeLa and 620.59 μg/mL for A549 [36].

Cydonia oblonga Mill. (Rosaceae)

The potential antitumoral effect of peel and pulp polyphenolic extracts from C. oblonga fruit on human colon adenocarcinoma cells (LS174) and both non-tumorigenic cells (NIH 3T3 and HEK 293) was investigated by Riahi Chebbi et al. [37]. Results showed that aqueous acetone peel extract displayed the highest antiproliferative activity, specifically on LS174 cells (IC50=5 µg/mL), without any toxic effect. Phenolic components level in the peel fraction is three times higher than the pulp. Phytochemical investigations led to the identification of 13 phenolic compounds in aqueous acetone peel extract which were quercetin, rutin, (+)-catechin, (−)-catechin, hyperin, isoquercitrin, chlorogenic acid, cryptochlorogenic acid, neochlorogenic acid, p-coumaric acid, kaempferol, kaempferol-3-O-glucoside and kaempferol-3-O-rutinoside [38]. However, the use of commercially purified compounds had indicated that each peel phenolic compound alone did not exhibit any antiproliferative activity, suggesting a synergistic effect of phenolic molecules. Such effect was associated with a cell cycle arrest in the G1/S phase, a caspase-independent apoptosis and an increase of the production of intracellular reactive oxygen species. Peel extract inhibited the pro-survival signaling pathway NFκB and suppressed the expression of various cellular markers known to be involved in cell cycling and angiogenesis. Interestingly, the combination peel extract and chemotherapeutical agent 5-FU exerted synergistic inhibitory effect on cell viability [37].

Cynodon dactylon L. (Poaceae)

The anticancer activity of petroleum ether, dichloromethane, acetone, methanol/water (3/1) and water extracts from C. dactylon L. were evaluated against human breast adenocarcinoma cell line (MCF-7). The strongest activities were obtained by the water extract (IC50=57.21 mg/L), the acetonic extract (IC50=38 mg/L) and the petroleum ether extract (IC50=39 mg/L), respectively. The results indicated a good correlation between anthocyanins quantity and the anticancer activity (R2=0.78). The LC–MS analysis of the extracts having the good activities anticancer has revealed, for the first time in this plant, the presence of seven anthocyanins, namely delphinidin-3-O-acetylglucoside, petunidin-3-O-caffeoylglucoside-5-O-glucoside, petunidin-3-O-coumarylglucoside-5-O-glucoside, malvidin-3-O-monoglucoside, delphinidin-3-O-acetylglucoside-pyruvic acid, petunidin-3-O-acetylglucoside-5-O-glucoside and cyanidin-3,5-O-diglucoside [39].

Cyperus rotundus L. (Cyperaceae)

The lyophilized infusion, total oligomer flavonoid, ethyl acetate and methanol extracts of C. rotundus tuber were investigated for their in vitro cytotoxic effect against murine lymphoblastic leukemia (L1210) cells using the calorimetric MTT assay. The tested malignant cells showed a good response to the effect of total oligomer flavonoid (IC50=240 µg/mL) and ethyl acetate (IC50=240 µg/mL) extracts. However, the lyophilized infusion and methanol extract had a negligible cytotoxic effect on L1210 cells. The strong cytotoxic activity of total oligomer flavonoid and ethyl acetate extract from C. rotundus tuber may be attributed to the presence of specific components such as coumarins, flavonoids and total polyphenols [41]. In other study, Kilani Jaziri et al. [40] had studied the in vitro cytotoxic effect of total oligomer flavonoid and ethyl acetate extract from C. rotundus aerial part as well as its three isolated pure components (ferulic acid, luteolin and catechin) on the human chronic myelogenous leukemia cells (K562) using the MTT assay. Results showed that luteolin exhibited a stronger cytotoxic activity against K562 cells (IC50=25 µg/mL) than ethyl acetate extract (IC50=100 µg/mL), from which it was isolated. Thus, it is proposed that the presence of this compound contributed to the cytotoxic activity of the original extract. On the other hand, the total oligomer flavonoid enriched extract had the strongest cytotoxic activity (IC50=70 µg/mL), but the catechin isolated from this extract, was less active (IC50>800 µg/mL). Thus, it was proposed that other compounds in total oligomer flavonoid (with or not catechin synergy) might participate to the inhibitory effect [40].

Daphne gnidium L. (Thymelaeaceae)

The antiproliferative potential of chloroform, methanol and butanol extracts from D. gnidium leaf on B16-F0 and B16F-10 melanoma cells was assessed. Cell viability was determined using the MTT assay. Results showed that chloroform extract D. gnidium leaf exhibited significant antiproliferative activity toward the two types of tumor skin cells. However, methanol and butanol extracts showed a significant antiproliferative effect only on B16-F0 cells. This anti-proliferative activity D. gnidium leaf may be attributed to the presence of specific bioactive components [42]. Deina et al. [141] showed the presence of four coumarins (daphnetin, daphnin, acetylumbelliferon and daphnoretin), nine flavonoids (apigenin, luteolin, quercetin, orientin, isoorientin, luteolin 7-O-glucoside, apigenin 7-O-glucoside, genkwanin and 5-O-β-d-primeverosyl genkwanine) and α-tocopherol in methanol extract of D. gnidium leaf. Coumarins, especially daphnetin, showed a great antiproliferative activity in several tumor cell lines such as A-498 human renal cell carcinoma cells [142] and MCF-7 estrogen-responsive human carcinoma cells [143]. The association between flavonoids and reducing cancer risk has been related to the consumption of vegetables and fruits which were source of flavonoids. In fact, apigenin, a common dietary flavonoid, had inhibited the proliferation of human ovarian cancer (A2780) cells [144]. Luteolin exhibited a stronger cytotoxic activity against K562 human chronic myelogenous leukemia cells [40]. Quercetin had induced antiproliferative activity against Hep G2 human hepatocellular carcinoma cells [138]. The effect of orientin on the growth and apoptosis of esophageal cancer EC-109 cells had proven by An et al. [145]. The flavonoid genkwanin had significantly inhibited HT-29 and SW-480 human colorectal cancer cell proliferation [146]. Concerning α-tocopherol, it is the most biologically active form of vitamin E which has anticarcinogenic activities and it may be a suitable candidate for the adjuvant treatment of cancer. The chemopreventive properties of vitamin E were first suspected when studies showed that people in the Mediterranean area, who consume diets rich in vitamin E, have a lower risk of colon cancer than people in Northern Europe and USA [147]. Further support for the possible use of vitamin E in cancer chemoprevention came from another study, which showed that low nutritional intake of vitamin E increases prostate cancer risk supporting the possible use of this nutrient in the chemoprevention of prostate cancer [148].

Datura metel L. (Solonaceae)

The cytotoxicity of the aqueous methanolic extract from D. metel leaves was assessed against human lung carcinoma (A549), colorectal adenocarcinoma (DLD-1) and normal skin fibroblast (WS1) cell lines using a resazurin assay. The aqueous methanolic extract was cytotoxic against A549 (IC50=11.9 µg/mL), DLD-1 (IC50=3.1 µg/mL) and WS1 (IC50=7.9 µg/mL) cells. A bioguided fractionation of the aqueous methanolic extract was conducted in order to isolate and identify the compounds responsible for the cytotoxicity activity. The withanolide-type steroids, namely daturamalakoside A, daturamalakoside B, daturametelin A, daturametelin B and withametelin, were isolated and tested against human lung carcinoma (A549) cells and human colorectal adenocarcinoma (DLD-1) cells. Etoposide and camptothecin were used as positive controls with IC50 values respectively of 7 and 0.11 µM for A549 and 4 and 0.31 µM for DLD-1. Daturametelin B and Withametelin compounds were found to be strongly cytotoxic against DLD-1 cells (IC50=0.6–0.7 µM) and their activities were significantly higher than etoposide and compounds daturamalakoside, daturamalakoside B, daturametelin A and slightly lower than the camptothecin. The results showed that new daturamalkoside withanolides and the known daturametelin A compound were moderately active against DLD-1 with IC50 values of 17 and 24 µM, respectively. Interestingly, the new daturamalkoside B was also found to be strongly active against DLD- (IC50=2 µM) with a cytotoxicity higher than etoposide with IC50=4 µM [43].

Echballium elaterium L. (Cucurbitaceae)

The cytotoxic effect of E. elaterium seed oil on the growth of human colonic adenocarcinoma (HT29) and fibrosarcoma (HT1080) cell lines was evaluated using the MTT assay. The E. elaterium seed oil was cytotoxic against both tumor cell lines HT29 and HT1080. This cytotoxic effect was dose-dependent with IC50=4.86 µg/mL for HT29 and 4.16 µg/mL for HT1080. To find bioactive compounds responsible of anticancer activity, the chemical composition of E. elaterium seed oil was found to be a rich source of polyunsaturated fatty acid, especially linoleic and punicic acids [44]. Linoleic acid has been reported to have significant activity in inhibiting mammary carcinogenesis [149]. It also suppressed the proliferation of human breast adenocarcinoma (MDA-MB468) cells in SCID mice [150]. E. elaterium was the only species in the Cucurbitaceae family characterized by the presence of punicic acid in seed oil. Punicic acid isolated from Punica granatum has been found to have antiproliferative activity against breast cancer (MDA-MB-231) cell line and it induced apoptosis in breast cancer cell lines [151]. E. elaterium seed oil was also characterized by the occurrence of monounsaturated fatty acids, such as oleic acid (18:1n-9), that play an active role in the prevention of human cancer. Oleic acid, the main monounsaturated fatty acid of olive oil, enhances the growth inhibitory effects in breast cancer cell lines SK-Br3 and BT-474 [152]. The β-Sitosterol was the major phytosterol in E. elaterium seed oil and it has displayed antiproliferative activity against colonic cancer COLO 320 DM cell lines [153]. Among tocopherols, γ-tocopherol was the major one and it showed a great ability to inhibit proliferation of prostate and lung cancer cells by interrupting the sphingolipid pathway synthesis [154]. Additionally, the presence of a high level of carotenoids in E. elaterium seed oil which are beneficial due to their protection effect against the development of cancer [155].

Eugenia caryophyllata L. (Myrtaceae)

The cytotoxicity assay of E. caryophyllata essential oil on cancer cell lines, namely human colon cancer (HT29), human lung epithelial carcinoma (A549), human laryngeal carcinoma (Hep2) murine macrophage raw (264.7) and noncancerous human fetal fibroblast (MRC-5) was determined using the MTT assay. Results showed that E. caryophyllata essential oil showed significant cytotoxic effects against all studied cancer cell lines as judged by IC50 ranging from 15.75 to 200 μg/mL [45]. It is known that the name of the main constituent of E. caryophyllata essential oil, eugenol, is derived from this species name. As the main component, eugenol isolated from E. caryophyllata essential oil had induced a reactive oxygen species-mediated apoptosis in human promyelocytic leukemia HL-60 cell line [156].

Euphorbia paralias L. (Euphorbiaceae)

The cytotoxicity effect of methanol and chloroform fractions from E. paralias shoot was examined toward human acute myeloid leukemia (THP1) and human colon epithelial (CaCo2) cancer cell lines, as well as CD 14 and IEC-6 normal cells using the MTT assay. E. paralias polar fraction was highly active against THP1 cells, with IC50=54.58 µg mL−1. However, no cytotoxicity was found against normal cells (CD14+ monocytes), owing to the potent selective anticancer effect of E. paralias extract against leukemia cells [46]. The phytochemical analysis of E. paralias extract has led to the isolation of new segtane diterpenoids having anticancer effect [47].

Euphorbia terracina L. (Euphorbiaceae)

The cytotoxicity effect of methanol and chloroform fractions from E. terracina aerial part was investigated toward human acute myeloid leukemia (THP1) and human colon epithelial (Caco2) cancer cell lines, as well as CD 14 and IEC-6 normal cells by targeting various modulators of apoptosis or inflammation. Results showed that E. terracina polar and apolar fractions were highly active against THP1 cells with IC50=2.08 and 14.43 µg mL−1, respectively. The two fractions induced apoptosis in THP1 cell line after 6 h of exposure. Apoptosis caused by apolar fraction was related to a caspase-dependent process, whereas other death pathways seemed to be involved with the polar fraction. An enhanced production of reactive oxygen species was detected upon cell treatment with E. terracina extract. Interestingly, they have no effect on cytokine TNF-a secretion in THP1 and normal cells compared to untreated cells, indicating that the two fractions caused no inflammation [46]. No cytotoxicity was found against normal cells (CD14+ monocytes) which revealed that E. terracina has potent selective anticancer effects on leukemia cells, accordingly to El Manawaty et al. [157] which indicated the antigrowth and cytotoxic effects of methanol extract of E. terracina against human hepatocellular carcinoma cell line (HepG2). The potent anticancer activity of E. terracina could be due to its richness in phenolic compounds and terpenoids [46].

Ferula communis L. (Apiaceae)

The cytotoxicity effect of F. communis essential oils from different organs, namely flower, root, leaf and stem, was evaluated on A549 lung epithelial carcinoma and HeLa cervix cell lines using the MTT assay. The most important activity of samples of both cells was at 500 µg mL−1. All organs present an interesting cytotoxic activity on HeLa cells more than on A 549 cells which could suggest a specificity of action toward cell type. The best inhibition proportion on HeLa cells was shown with stem essential oils with 79.05 %. The flower essential oil presented 74.89 % of inhibition on HeLa cells [48]. The F. communis flower essential oil was rich in camphor (18.3 %) and α-pinene (15.3 %) monoterpenes which have been described by Sobral et al., 2014 for their potential anticancer activities. The chemical composition of F. communis stem essential oil was characterized by its richness in β-eudesmol (28.1 %) and α-eudesmol (9.6 %). In fact, Britto et al. [158] had mentioned that Guatteria friesiana essential oil presented an interesting potential for its α- β and γ-eudesmol components against tumor cell lines.

Ferula lutea L. (Apiaceae)

The anticancer effect of ethyl acetate and n-butanol extracts from F. lutea flower against the leukemia cancer K562 cell Line was determined using the MTT assay. The cytotoxicity of the n-butanol extract (IC50=40 μg/mL) was superior to that of ethyl acetate (IC50>100 μg/mL), but not very high compared to the doxorubicin standard substance with IC50=0.1 μg/mL [49]. A phytochemical investigation of the n-butanol extract from F. lutea flower has led to the isolation of a new compound, (E)-5-ethylidenefuran-2(5H)-one-5-O-β-D-glucopyranoside, designated ferunide, 4-hydroxy-3-methylbut-2-enoic acid, reported for the first time as a natural product, together with nine known compounds divided in five phenolic compounds (5-O-caffeoylquinic acid, methyl caffeate, methyl 3,5-O-dicaffeoylquinate, 3,5-O-dicaffeoylquinic acid, isorhamnetin-3-O-α-L-rhamnopyranosyl(1→6)-β-Dglucopyranoside and narcissi), two furanocoumarins (marmesin and isoimperatorin) and two volatile derivatives (verbenone-5-O-β-D-glucopyranoside and 2,3,6-trimethylbenzaldehyde). The cytotoxic activity of isolated compounds against HCT-116 human colon cancer, IGROV-1 and OVCAR-3 human ovary cell lines was evaluated using the MTT assay. Only the methyl caffeate compound was found to be the most cytotoxic, with IC50=22.5 μmol/L against HCT-116, 17.8 μmol/L against IGROV-1 and 25 μmol/L against OVCAR-3 [104].

Ferula tunetana Pom. (Apiaceae)

A two new compounds, tunetanin A (Sesquiterpene ester) and tunetacoumarin A (sesquiterpene coumarin), as well as eight known compounds, coladin, coladonin, isosmarcandin, 13-hydroxyfeselol, umbelliprenin, propiophenone, beta-sitosterol and stigmasterol, were isolated from F. tunetana root. The cytotoxicity activity of each isolated compound towards two human colon cancer cell lines, HT-29 and HCT 116, was evaluated. Compounds coladin, coladonin and 13-hydroxyfeselol showed weak cytotoxic activities [50].

Globularia alypum L. (Globulariaceae)

The cytotoxic effect of hydroethanolic extract from G. alypum leaf against human epithelial cervical cancer (HeLa) cell line was investigated using the MTT assay. Data showed that the hydroethanolic extract of G. alypum leaf displayed inhibition effect on human cell growth at a dose-dependent manner with IC50=1.53 mg/mL [51]. The anticancer capacity of G. alypum extract was related to its bioactive compounds which were mainly divided in flavonoid glycosides (luteolin), in phenylethanoid glycosides (acteoside, isoacteoside and forsythiaside) [52] and in iridoid glucosides (globularioside, globularin, globularicisin, globularidin, globularinin and globularimin) [159].

Hammada scoparia Pomel (Chenopodiaceae)

The cytotoxicity effect of aqueous ethanolic extract and flavonoid enriched fraction from H. scoparia leaf against leukemic (U937, HL-60, KG1 and KG1a) cell lines in suspension or in adhesion was evaluated using the MTT assay. Results showed that the most leukemic cell lines displayed stronger sensitivity to treatment with the aqueous ethanolic extract from H. scoparia leaf under adherent conditions. In contrast, the highly chemoresistant cell line KG1a remained unchanged by the treatment with the H. scoparia extract. The flavonoid enriched fraction was cytotoxic for both leukemic cells in adhesion or suspension. Interestingly, adherent leukemic cells from acute myeloid leukemia patients showed an efficient reduction in survival whereas peripheral blood mononuclear cells and normal immature hematopoietic cells were not sensitive to the treatment with flavonoid-enriched fraction. The selective bioactivity of this fraction served to search its responsible bioactive compounds [36]. The chemical composition of H. scoparia leaf was characterized by the presence of nine alkaloides (salsolinol, isosalsoline, N-methylisosalsoline, salsolidine, carnegine and N-methylcorydaldine, tryptamine, N-methyltryptamine and norsynephrine) and five flavonol glycosides (Isorhamnetin 3-O-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→6)-β-D-galactopyranoside, isorhamnetin-3-O-D-d-robinobioside, isorhamnetin-xylose-galactose, quercetin-xylose-rhamnose-galactose and quercetin-glucose-rhamnose (rutin)). The anti-leukemic activity of several alkaloids and flavonoids present in the flavonoid enriched fraction from H. scoparia. Alkaloids were found cytotoxic on U937 in suspension as well as in adhesion, several flavonoids displayed a cytotoxic activity more specific of the adhesion status of leukemic cells and among them, rutin was the most potent and showed a qualitatively similar cytotoxicity to the flavonoid fraction on U937 [53]. Rutin increased the cytotoxicity on adherent leukemic cells but counteracted daunorubicin-induced cell death of U937 in suspension, and cell adhesion-mediated drug resistance was abolished. Addition of rutin to U937 cells already adherent onto fibronectin is still able to trigger cell death [53]. However, when rutin and daunorubicin were incubated simultaneously on adherent cells, no additive or synergic effects on cytotoxicity were presented and they deduced that the specific cytotoxic activity of H. scoparia extract in adherent leukemic cells could be partially due to its rutin content [53].

Jatropha podagrica Hook (Euphorbiaceae)

The anti-proliferative effect of hydro-alcoholic extract from J. podagrica leaf on two tumoral cell lines human lung adenocarcinomic (A549) and rat pheochromocytoma (PC12) cells was assessed by the MTT assay. The two lines presented a high susceptibility to J. podagrica extract. Treatment concentrations greater than 12 µg/mL presented a dose-dependent reduction in cell viability greater than 20 %. At the highest concentration evaluated, the reduction in cell viability was greater than 80 %. J. podagrica extract was cytotoxic even at low concentration and the cell viability response was concentration dependent [54]. Liu et al. [55] had isolated 11 diterpinoids from J. podagrica leaf which were epi-isojatrogrossidion, jatrogrossidion, 4E-jatrogrossidentadion, Jatrophodion A, ent-3β-hydroxypimara-8,15-dien-12-one, clemaphenol A, (+)-medioresinol, scoparone, fraxidin, 7,8-dihydroxy-5,6-dimethy-2H-1-benzopyran-2-one and (3R,8S)-falcarindiol. Many of these diterpenes showed in-vitro cytotoxic activity. In fact, 4E-jatrogrossidentadion, isolated from J. curcas, was highly active against mouse lymphoma (L5178y) cells and human cervix carcinoma (HeLa) cells [160]. Scoparone, isolated from Artemisia capillaries, had exerted anti-tumor activity against prostate cancer (DU145) cells via inhibition of STAT3 activity [161]. The antitumor natural compound falcarindiol, isolated from Oplopanax horridus root bark, had promoted cancer cell death by inducing endoplasmic reticulum stress [162]. Additionally to diterpenes, it is possible that the presence of other compounds in J. podagrica extract responsible of its antitumoral effect. So, Thomas [163] recently reported that J. podagrica leaf was rich in flavonoids (apigenin, acacetin and luteolin), phenolic acids (vanillic, syringic, melilotic, ferulic and p-coumaric acids), tannins and steroids.

Juglans regia L. (Juglandaceae)

The antiproliferative effect of J. regia bark ethanol extract was evaluated on normal (MRC-5) and cancer (HT29 and HEp-2) cell lines. Results showed that J. regia bark ethanol extract exhibited antiproliferative effects with IC50 ranging from 6.6 to 25.5 μg/mL [56]. This species has an aromatic phytochemical juglone found in all parts including the leaves, roots, stem, branches and nuts [57]. Juglone has been reported as an important therapeutic phytochemical and it has been investigated for its carcinogenic/anti-carcinogenic effects. In fact, juglone has shown effective results against both human leukemia (HL-60) cells and doxorubicin-resistant human leukemia (HL-60R) cells [58]. In juglone-treated tumors, chromosomes in the prophase stage of cell division appeared diffused and sticky, and accumulation of abnormal metaphase figures occurred. Sugie et al. [59] reported that male rats on a juglone-rich diet had a lower incidence and multiplicity of tumors in the small intestine. Recent studies showed that juglone-induced cell apoptosis through the mitochondria‐dependent pathway in human lung cancer (A549) cells [60], human leukemia (HL‐60) cells [61] and human cervical carcinoma (HeLa) cells [62]. Fang et al. [63] had also proven that juglone exerted antitumor effect in ovarian cancer (SKOV3) cells.

Lawsonia inermis L. (Lythraceae)

The antitumor activity of hexane, chloroform and methanol extracts from L. inermis flower against human colon cancer (HCT-116) cells was determined using the MTT assay. The chloroform fraction had the stronger anticancer activity with IC50=21 mg/L. The methanol extracts were weaker with less growth inhibition of HCT-116 cells (IC50=50 mg/L). So, chloroform was the better solvent for more extraction of anticancer compounds from L. inermis flower as compared to the other solvents [64]. Among these bioactive compounds, Arun et al. [65] said that lawsone (2-hydroxy-1,4-naphthoquinone) is an active naphthoquinone derivative isolated from L. inermis leaf which gives the cytotoxic properties. Another work indicated that lawsone is chief coloring component of L. inermis leaf and it is not mutagenic, but toxic to the cells in dose-dependent manner [66].

Limoniastrum guyonianum Boiss. (Plumbaginaceae)

The aqueous extract of L. guyonianum gall exhibited anticancer effect against mice melanoma (B16F10) cells both in vitro and in vivo. It may be assumed that much of the anti-tumor activity of G extract could likely be ascribed to several compounds in the extract [67]. Preliminary results of phytochemical screenings revealed a presence of tannins, polyphenols and flavonoids [164]. With regard to the former, flavonoids like epigallocatechin gallate present in the extract are considered to be some of the most active anti-tumor derivatives found in plants [165, 166, 167]. It was reported that the intravenous administration of epigallocatechin gallate encapsulated in transferrin-bearing vesicles resulted in tumor suppression in 40 % of B16-F10 tumors in vivo [168]. Indeed, it has been reported that flavonoids present in L. guyonianum extract exert apoptotic effects in vitro and can stimulate immune responses [164, 165, 166, 167, 168, 169].

Limonium densiflorum Kuntze (Plumbaginaceae)

The cytotoxicity of hexane, dechloromethane, methanol and ethanol extracts from L. densiflorum shoot was evaluated against human colon carcinoma (DLD-1), human lung carcinoma (A-549) and human skin fibroblast (WS-1) cell lines. Dichloromethane extract displayed an interesting cytotoxic activity against A-549 (IC50=29 μg/mL) and DLD-1 (IC50=85 μg/mL). L. densiflorum shoot extract showed a chemical profile composed by seven identified phenolic compounds, including gallic acid, catechin hydrate, sinapic acid, trans 3-hydroxycinnamic acid, ellagic acid, myricetin and isorhamnetin. The attendance of these compounds in shoot extracts approved the interesting anticancer activity of this species [68]. In fact, the phenolic gallic acid compound has been reported for its antiproliferative activity against many cancer cell lines such as human lung adenocarcinoma (A549) cell line [170], human colon cancer (HCT15) and human breast cancer (MDA MB 231) cell lines [171]. Manikandan et al. [140] had reported that catechin inhibited the growth of human colon adenocarcinoma HCT 15, HCT 116 and human larynx carcinoma (Hep G-2) cell lines. Balaji et al. [172] had proven the anticancer effect of sinapic acid on human colon cancer cell lines HT-29 and SW480. McCann et al. [173] demonstrated that the hydroxycinnamic acids components of apples were linked to inhibition of colon cancer in vitro. Edderkaoui et al. [174] had indicated that ellagic acid at low concentrations (0.5–3 µM) triggered the apoptosis and inhibited the proliferation of the human pancreatic cancer (MIA PaCa-2 and HPAF-II) cell lines cells. Concerning myricetin, it had a potential anticancer activity in human T24 bladder cancer cells both in vitro and in vivo [175]. For isorhamnetin, it could significantly inhibit the invasion of human breast (MDA MB 231) cells [176].

Lycium europaeum L. (Solanaceae)

The antiproliferative activity of the hydro-alcoholic extract from L. europaeum fruit was investigated. Results showed that L. europaeum extract exhibited the ability to reduce cancer cell viability, inhibit proliferation and induce apoptosis in A549 human lung cancer cells and PC12 rat adrenal medulla cancer cells in a concentration and time-dependent manner. L. europaeum fruit was characterized by the presence of polyphenol, flavonoid, carotenoid and tannin compounds which could be contributed at the anticancer activity [69].

Marrubium vulgare L. (Lamiaceae)

The cytotoxicity effect of M. vulgare shoot essential oil on human cervical cancer (HeLa) cell lines was studied using the MTT assay. M. vulgare essential oil significantly decreased the viability of HeLa in a dose-dependent manner. For a concentration up to 250 μg/mL, M. vulgare essential oil destructed HeLa cells by 27 %, however for a concentration higher than 500 μg/mL, all HeLa cells were destructed. At lower doses, M. vulgare essential oil was tolerated by the cells with IC50=0.258 μg/mL [70]. The cytotoxicity of the tested essential oils may be due to the presence of some monoterpenes and sesquiterpenes including α-humulene [177] and isoprenoids including geraniol [178]. These compounds were reported to be active against the tumor cell lines, but in M. vulgare essential oil, they exist in small amount [179]. The predominant compounds of M. vulgare essential oil were γ-eudesmol (11.93 %), β-citronellol (9.90 %), citronellyl formate (9.50 %) and germacrene-D. In fact, Setzer et al. [128] reported that germacrene D has exhibited a seven-fold stronger cytotoxic activity against the Hs 578T cell line in comparison with α-pinene and limonene and a six-fold stronger action against Hs 578T and Hep-G2 than 1,8-cineole, linalool, 4-terpineol and α-terpineol. Zhuang et al. [180] reported that citronellol, an essential oil soluble compound, derived from Geranium, has anticancer activity. An interesting potential against tumor cell lines was effected by Guatteria friesiana essential oil due to its α- β and γ-eudesmol components [46].

Melaleuca armillaris Sm. (Myrtaceae)

The anticancer activity of essential oil from M. armillaris leaf was evaluated against human breast cancer (MCF7) cell line. M. armillaris leaf essential oil was very active against MCF7 with IC50=12 μg/mL. The chemical composition of M. armillaris leaf essential oil was rich in 1,8-cineole with 85.8 %, camphene with 5.05 % and α-pinene with 1.95 % [71]. These main monoterpene compounds (93 %) were found to play an important cytotoxic role against several cancerous cell lines. In fact, the monoterpene 1,8-cineole demonstrated moderate cytotoxicity in Hep G2, HeLa, MOLT-4, K-562, and CTVR-1 cell lines [181]. The cytotoxicity of 1,8-cineole was investigated against SK-OV-3, HO-8910, and Bel-7402 cell lines [182]. Murata et al. [183] indicated that 1,8-cineole had suppressed human colorectal cancer proliferation by inducing apoptosis. The monoterpene camphene, isolated from Piper cernuum essential oil, had induced intrinsic apoptosis in melanoma cells and had displayed antitumor activity in vivo [184]. The cytotoxicity of the monoterpene α-pinene was comparable to the control doxorubicin [185]. The cytotoxic potential of α-pinene was investigated in SK-OV-3, HO-8910, Bel-7402 [182] and U937 cell lines [186].

Moricandia arvensis L. (Brassicaceae)

The cytotoxicity effect of chloroform and ethyl acetate extracts from M. arvensis leaf and root against human chronic myelogenous leukemia cell line K562 was determined using the MTT assay. The best reducing power accompanies the best inhibition of cancerous cell viability in the presence of root extracts. The presence of an important anticancer activity in chloroform root extract compared to chloroform leaf extract and in ethyl acetate root extract compared to ethyl acetate leaf extract may be ascribed to their high quantity of polyphenols [72]. On the other hand, many reports demonstrated the ability of polyphenols to inhibit cancer cell proliferation in vitro and several antioxidants in plants have been suggested to contribute to the anticarcinogenic effect [187].

Nigella sativa L. (Ranunculaceae)

The anticancer activity of N. sativa essential oil was evaluated against human lung carcinoma (A-549) and colon adenocarcinoma (DLD-1) cell lines. N. sativa essential oil was active against A-549 (IC50=43 μg/mL) and DLD-1 (IC50=43 μg/mL). The chemical composition of N. sativa essential oil was rich in p-cymene (60.5 %), α-thujene (6.9 %), thymoquinone (3 %), β-pinene (2.4 %) and carvacrol (2.4 %). The cytotoxicity assessment of the main compounds present in the essential oil showed that thymoquinone was the most active to inhibit tumor cell growth with IC50=2.1 μg/mL for A-549 and IC50=1.0 μg/mL for DLD-1. However, p-cymene, α-thujene, β-pinene and carvacrol exhibited weak activities against A-549 and DLD-1 cell lines. Concerning the positive etoposide control, it exhibited IC50 values of 2.0 μg/mL against A-549 and 15.9 μg/mL against DLD-1 [73]. Jrah Harzallah et al. [74] had also studied the cytotoxic effect of N. sativa essential oil and thymoquinone on human epithelial (Hep-2) cell line. Results showed that the growth inhibition effect of thymoquinone (IC50=19.25 µg/mL) on Hep-2 cell line was significantly stronger than the essential oil (IC50=55.20 µg/mL).

Nitraria retusa Forssk. (Zygophyllaceae)

The effect of methanolic extract from N. retusa leaf on melanoma (B16-F10) cell growth was examined using the MTT assay. Results showed that methanolic extract of N. retusa leaf inhibited melanoma cell proliferation in a dose-dependent manner. Furthermore, methanolic extract of N. retusa leaf significantly suppressed growth of tumor cells in the tumor-bearing mice. This cytotoxicity may be ascribed to the presence of specific components such as polyphenols and flavonoids [75]. In earlier study, Boubaker et al. [105] reported that hexane extract of N. retusa leaf showed the highest growth inhibition of human chronic myelogenous leukemia cell line (K562) with IC50=9300 μg/mL as compared to chloroform and methanol extracts, and they attributed the highest activity of hexane extract to the presence of sterols in the extract. However, Mohamed et al. [188] reported that the highest cytotoxic effects of hexane extract from N. retusa leaf against five human carcinoma cell lines, namely human lung carcinoma (A-549), human colon cancer (HCT-116), human breast cancer (MCF-7), human prostate cancer (PC-3) and human liver carcinoma (HEPG-2), can be clarified partly by the presence of high concentration of some phenolic compounds such as butylated hydroxyltoluene and 3-tert-butyl-4-hydroxy anisole which are known to possess cytotoxic activity [189]. Besides, the hexane extract of N. retusa leaf was also characterized by the presence of hydrocarbon compounds like 17-pentatriacontene and docosane which presented cytotoxic effects against different cell lines [190, 191].

Olea europea L. (Oleaceae)

O. europea leaf extract, obtained from the Tunisian olive variety “El Hor” using supercritical fluid extraction, was shown to have significant antiproliferative capacity on JIMT-1 breast cancer cells with IC50=7 µg/mL [76]. In this work, Barrajón Catalán et al. [76] had identified metabolites that may account for the antiproliferative mechanism of an olive leaf extract which were derivatives of three flavones: luteolin, diosmetin and apigenin. Among these flavones, pure luteolin exerted the strongest antiproliferative capacity on breast cancer (JIMT-1) cells (IC50=17.2 µg/mL). The luteolin cytotoxicity level was followed by apigenin (IC50=99.0 µg/mL) and diosmetin (IC50=107 µg/mL). Nevertheless, none of the flavones exhibited an IC50 value close to that determined for the olive leaf extract. In fact, a plausible explanation could be that non-identified or minor compounds in the extract could partially contribute acting at the membrane level. Another possible explanation is that the flavones may act in a synergistic manner to achieve the antiproliferative effects of the extract, which deserves further attention by fractionation or synergic studies [76].

Ononis angustissima L. (Fabaceae)

The essential oil of O. angustissima aerial part was tested for its possible cytotoxic activity toward the human cervical adenocarcinoma (HeLa) cell line using the MTT assay. The essential oil of O. angustissima aerial part was found to be able to inhibit the HeLa cell growth with IC50=0.53 mg/mL after 72 h which could be due to its richness in oxygenated sesquiterpenes with 33.2 % [77]. In fact, the presence of α-eudesmol in an appreciable amount (22.4 %) and γ-eudesmol (1.4 %) both isomers of β-eudesmol unidentified in O. angustissima essential oil and considered active against HeLa cells [192, 193, 194]. Moreover, it has been shown that sesquiterpene rich essential oils and pure sesquiterpenes, such as ß-caryophyllene forming only 1.7 % in O. angustissima essential oil, have a high cytotoxicity against HeLa cell line as the case of Zanthoxylum rhoifolium [195]. Nonetheless, besides the contribution of specific constituents, Ghribi et al. [77] mentioned that the synergism between various components of the essential oil could play an important role in the cytotoxic effect verified in this study against HeLa cell.

Opuntia ficus indica L. (Cactaceae)

The aqueous-acetone extract prepared from the Tunisian O. ficus-indica fruit syrup was investigated for its cytotoxicity activity against the human tumorigenic SH-SY5Y neuroblastoma and non-tumorigenic 3T3 fibroblast cells. The analyzed syrup extract has a pronounced cytotoxic effect on eukaryotic cells, particularly with higher potential against tumorigenic than non-tumorigenic cells [78]. O. ficus-indica fruit syrup was found to be a good source of natural phenolics with the predominance of isorhamnetin derivatives having anticancer effects. In fact, Antunes Recardo et al. [196] had proven that different isorhamnetin derivatives, isolated from O. ficus indica pads, had induced apoptosis in two different human colon cancer (HT-29 and Caco2) cells. Additionally, Kim et al. [197] reported that isorhamnetin compound had suppressed skin cancer through direct inhibition extracellular signal regulated kinase 1 and phosphoinositol 3-kinase signaling pathways.

Origanum majorana L. (Lamiaceae)

The in vitro cytotoxicity bioassays of O. majorana shoot essential oil against two human tumor (Hep2 and HT29) cell lines and one continuous cell lineage control (Vero) were determined by the MTT assay. Results showed that the cytotoxicity activity of O. majorana essential oil against HT29 (IC50=13.73 mg/mL) was more important than Vero (IC50=70.13 mg/mL) and Hep2 (IC50=85.63 mg/mL) cell lines [79]. The cytotoxic activity of O. majorana essential oil might be in part due to the presence of some components in high percentages, such as terpinen-4-ol (23.2 %), which was also reported to possess a high antitumor activity against breast cancer, colon cancer, gastric cancer cells, and lung, ovarian and laryngeal cancer cell lines [198]. Some components, such as β-Caryophyllene weakly present (2.1 %) in O. majorana essential oil, have previously been reported to have potent cytotoxic activity against MCF-7, MDA-MB-468 and UACC-257 cell lines [199] by enhancing the penetration of other bioactive components and then increasing the permeability of plasma membrane, thus increasing the overall essential oil cytotoxicity [198]. In fact, the cytotoxic activity should not be only attributed to major components; accounts for bioactivity should also take the synergistic effects between minor and major constituents into consideration [79].

Ormensis africana Jord. and Four. (Asteraceae)

The cytotoxic effect of hydroethanolic extract of O. africana inflorescence on human epithelial cervical cancer (HeLa) cell line was investigated using the MTT test. Data showed that hydroethanolic extract of O. africana inflorescence displayed an inhibition effects on HeLa growth in a dose-dependent manner with IC50=16.52 μg/mL. The hydroethanolic extract of O. africana inflorescence contained a considerable amount of polyphenol, flavonoid and anthocyanin compounds which contributed at significant anticancer activity [80].

Peganum harmala L. (Zygophyllaceae)

P. harmala seed had been evaluated for its cytotoxicity activity against human breast cancer (MCF7) cells using successive extraction solvents, namely petroleum ether, chloroform, ethyl acetate, ethanol and water. Results showed that ethanolic extract exerted the highest activities against human breast cancer cells MCF7 with IC50=32 mg/L [81]. However, Khlifi et al. [23] showed that the application of the aqueous methanolic extract from P. harmala seed against three human tumor cell lines, namely human bladder carcinoma (RT112), human laryngeal carcinoma (Hep2) and human myelogenous leukemia (K562), gave IC50 values inferior to 3 mg/L. Since ancient times, P. harmala has been used by traditional healers to make various preparations in the treatment of cancers and tumors in some parts of the world [82]. In fact, analytical studies on the chemical composition of the plant show that the most important constituents of this plant are β-carboline alkaloids such as harmalol, harmaline and harmine [200]. Administration of different β-carboline alkaloids isolated from P. harmala showed inhibitory effect against Lewis lung cancer (sarcoma-180 or HepA) in mice at rates of 15.3–49.5 % [82]. Several in vitro and in vivo studies have revealed that these cytotoxicity and antitumor effects of P. harmala are related to its interaction with RNA [201], DNA and its synthesis [202] and inhibition of human Topoisomerase [203]. In a study conducted in Iran, it was shown using the DNA relaxation assay that the extract of P. harmala inhibits human DNA Topoisomerase I. This effect was attributed to the β-carboline content of the extract and potency of the alkaloids were determined as harmine>harmane>harmaline in a way that treatment with the total extract showed weaker inhibitory effect than treatment with every individual alkaloid [203]. In another study, the effects of harmaline and harmalol were tested on digoxin-induced cytochrome P450 1A1 (CYP1A1), a carcinogen-activating enzyme, in human hepatoma HepG2 cells. These alkaloids significantly inhibited the enzyme via both transcriptional and posttranslational mechanisms in a concentration-dependent manner [204]. In some cases, P. harmala showed a higher selectivity toward malignant cells than common anticancer drugs like doxorubicin [205].

Phoenix dactylifera L. (Arecaceae)

The strong accumulation of phenolic compounds in the hydroalcoholic extract of leaves prompted us to investigate the anti-tumoral capacity of the plant extract on human melanoma (IGR-39) cells using the MTT assay. After treatment with hydroalcoholic extract of P. dactylifera leaves, significant inhibition of cell growth was observed at very high concentrations 18, 35 and 75 mg/mL. Obtained results suggest that leaves extract from P. dactylifera were significantly (p<0.001) active against the IGR-39 cells growth and had an interesting influence on IGR-39, indicating the presence of powerful cytotoxic compounds in hydroalcoholic extract, such as phenolic compounds [83]. In this respect, antitumor activity from several leaf extracts sources other than P. dactylifera has been reported [206, 207] and various studies showed that polyphenolic compounds affect cancer cell growth by inducing apoptosis in many cell lines like (CaCo-2, SW620, HT-29 and HCT-116) [205]. In addition, our results could be also explained by the presence of specific compounds on leaf, such as flavonoids glucosides (apigenin, quercetin), which are known by their cancer chemo-protective attributes [208, 209].

Pistacia lentiscus L. (Anacardiaceae)

The antiproliferative effect of P. lentiscus fixed oil and phenolic extract against baby hamster fibroblast (BHK21) cells was evaluated using the MTT assay. P. lentiscus seed oil showed potent antiproliferative effect with IC50=0.029 g/mL, whereas the phenolic extract produced an IC50 value of 0.15 g/mL in BHK21. The antiproliferative effect of P. lentiscus fixed oil is probably related to its fatty acid composition [84]. Studies on the biochemical composition of P. lentiscus oil have shown that it contained high amounts of oleic, palmitic and linoleic acids [210]. Several studies have shown that fatty acids inhibit cancer cell proliferation. Oleic acid, which is the major component of this oil, is known for its significant antiproliferative activity. Lior et al. [211] demonstrated that it causes cell apoptosis in some cancer cell lines. Furthermore, Pierre et al. [212] showed the significant anticancer effect of linoleic acid. This anti-proliferative effect against BHK21 cells could also be explained by the presence of antioxidants, such as tocopherols. Dhifi et al. [213] studied the biochemical composition of P. lentiscus seed oil and showed that it contained a large amount of α-tocopherol. This compound has been shown to induce cell death by apoptosis [214]. Chatelain et al. [215] linked the anti-proliferative effect of α-tocopherol to the inhibition of protein kinase C activity. In comparison with the fixed oil, the methanolic extract showed a lower anti-proliferative effect. This could be due to the anti-proliferative activity of phenols contained in the extract. This antiproliferative effect of phenols, which usually generates programmed death of cancer cells, depends on the nature of the phenolic compound [216].

Pituranthos tortuosus Desf. (Asteraceae)

Exposure of melanoma cancer (B16F10) cells in vitro to P. tortuosus shoot essential oil inhibited cell proliferation with IC50=80 μg EO/mL after 48 h. The anticancer activity of P. tortuosus essential oil could likely be ascribed to several compounds in the essential oil. GC-MS analysis revealed the richness of P. tortuosus essential oil in sabinene (24.24 %), α-pinene (17.98 %), limonene (16.12 %) and terpinen-4-ol (7.21 %). With regard to the former, terpinen-4-ol present in P. tortuosus essential oil is considered to be a very active anticancer agent [85]. It was reported that terpinen-4-ol exhibited in vitro and in vivo antimelanoma activity [86]. It has also been reported that the D- limonene significantly inhibited the growth and metastasis of gastric cancers in vivo [217]. Chen et al. [218] had proven the in vitro and in vivo inhibition of α-pinene, isolated from pine needle essential oil, on hepatoma carcinoma (BEL-7402) cells.

Punica granatum L. (Lythraceae)

The cytotoxic activity of hexane, dichloromethane, ethyl acetate, ethanol and methanol extracts from P. granatum leaf against breast cancer (MCF-7) cell line was assessed using MTT assay. Results showed that cytotoxicity activity of P. granatum leaf against MCF-7 varied markedly with solvent of extraction. Among the five solvent extracts, three P. granatum leaf extracts exhibited promising activity with IC50 values less than 50 mg/l. The methanolic extract presented the best cytotoxic effect with an IC50=31 mgL, followed by the ethanolic extract (IC50=33.50 mg/L) and ethyl acetate extract (IC50=45 mg/L). Hexane extract was poor active with IC50>100 mg/l. Thus, polar extracts were more cytotoxic than ethyl acetate and dichloromethane ones. The values of cytotoxic activity of methanolic, ethanolic and ethyl acetate are just good but not very high ones compared with the doxorubicin standard substance [87]. The cytotoxic activity of these extracts could be the result of a synergistic action of all or some components present in these extracts. P. granatum leaf was found to be rich in polyphenols with the main constituents were ellagic acid, brevifolin carboxylic acid, brevifolin, corilagin, apigenin derivatives, liteolin derivatives, granatin-B and punicafolin [88]. In agreement with Jurenka [219] had reported that extracts of all P. granatum parts (bark, fruit, leaf and root) appear to have medicinal benefit and the most therapeutically beneficial P. granatum constituents are ellagic acid ellagitannins (including punicalagins), punicic acid, flavonoids, anthocyanidins, anthocyanins, and estrogenic flavonols and flavones. In fact, Seeram et al. [220] had proven the potential effect of punicalagin, ellagic acid, total pomegranate tannins and P. granatum fruit juice in KB and CAL-27 oral cancer cell lines, as well as in HT-29 and HCT-116 colon cancer cell lines and several cell lines.

Raphanus sativus L. (Brassicaceae)

The 4-(methylthio)-3-butenyl isothiocyanate extracted from R. sativus root was tested for its in vitro cytotoxic activity against murine leukemia (L1210) cell line using the MTT cell proliferation assay. A decrease in L1210 growth at 24, 48 and 72 h was noted with increasing of 4-(methylthio)-3-butenyl isothiocyanate concentration with IC50=16 µM after 24 h [89].

Reaumuria vermiculata L. (Tamariaceae)

The anticancer capacity of hexane, dichloromethane, methanol and water extracts from R. vermiculata aerial part was evaluated against colon adenocarcinoma (DLD-1), human lung carcinoma (A-549) cell lines and healthy human skin fibroblast (WS1) cell line. Among the four solvent extracts, Karker et al. [90] had found that hexane and dichloromethane extracts exerted the most potent cytotoxic activity against A-549 with IC50=17 and 23 μg/mL, respectively, while a moderate cytotoxicity effect was observed for methanol (IC50=of 92 μg/mL) and water (IC50=77 μg/mL) extracts. However, the four extracts were inactive against DLD-1 (IC50>100 μM). Additionally, the four extracts were not cytotoxic against WS1. Karker et al. [90] had only identified four flavonoids in R. vermiculata aerial part which are myricetin, kaempferol-3-o-rutinoside, isorhamnetin-3-o-rutinoside and isorhamnetin. However, Nawwar et al. [91] had isolated 20 phenolic compounds from the aqueous methanolic extract of R. vermiculata aerial part with 16 Known compounds (2,6-digalloyl glucose, kaempferol 3,7-disodium sulfate, quercetin 3,7-disodium sulfate, gallic acid, 3‐mono methoxy ellagic 4-sodium sulfate, nilocitin, tamarixellagic acid, dehydrodigallic acid, decarboxy dehydrodigallic acid, quercetin, kaempferol, tamarixetin, ellagic acid, ellagic acid 3-monmethyl ether, ellagic acid 3,3′-dimethyl ether and 6-hydroxy 7-methoxycoumarine). Besides, three ellagitannins (3‐Methoxyellagic acid 4,4′-di-sulfate, 2-O-dehydrodigallic acid monocarboxyloyl-3-O-galloyl-(α/β)-glucose and vermiculatin) and one disulfated flavonol (tamarixetin 3,7-disulfate) were newly isolated. A potent cytotoxicity with IC50 less than 1 μg/mL was determined for two of the new isolated ellagitannins (3‐Methoxyellagic acid 4,4′-di-sulfate, 2-O-dehydrodigallic acid monocarboxyloyl-3-O-galloyl-(α/β)-glucose and vermiculatin) against the prostate cancer (PC-3) cell line. In addition, the aqueous methanolic extract of R. vermiculata aerial part exhibited a potential cytotoxic effect against four different solid tumor cell lines, namely liver (Huh-7), colorectal (HCT-116), breast (MCF-7) and prostate (PC-3) with IC50 ranged from 1.3 to 2.4 μg/mL.

Retama raetam Forssk. Webb (Fabaceae)

The two flavonoids licoflavone C and derrone isolated from R. raetam flower were tested for their in vitro cytotoxicity effects against human laryngeal carcinoma Hep-2 cell line using the MTT assay. The tested compounds showed strong cytotoxicity against Hep-2 with IC50=9 µg/mL for licoflavone C and IC50=30 µg/mL for derrone [92].

Rhamnus alaternus L. (Rhamnaceae)

The cytotoxic activity of petroleum ether, chloroform, ethyl acetate, methanol, water and total oligomer flavonoid extracts from R. alaternus aerial part against human chronic myelogenous leukemia (K562) cell line and leukemia murine (L1210) cells was investigated. A pronounced cytotoxic effect on both the cell lines was shown in the total oligomer flavonoid, ethyl acetate, methanol and aqueous extracts, with respectively IC50=75, 232, 298 and 606 μg/mL for K562 and 198, 176, 767 and 560 μg/mL for L1210 [221]. In another study, Ben Ammar et al. [93] had also found a pronounced antiproliferative effect on human leukemia (K562) cells was shown with flavonoid-enriched extracts from R alaternus root (IC50=165 μg/mL) and leaf (IC50=210.73 μg/mL). Boussahel et al. [222] had reported that the methanolic extract of Algerian R. alaternus bark (richer in kaempferol, rhamnocitrin and quercetin derivatives) decreased significantly the viability of leukemia (U937) cells with IC50=6.39 μg/mL. Additionally, kaempferol and rhamnocitrin glycosides from R. alaternus leaf have been demonstrated to induce apoptosis in human lymphoblastoid (TK6) cells [223] and quercetin can induce caspase-dependent cell death in U937 [224].

Ricinus communis L. (Euphorbiaceae)

The effect of different concentrations of essential oil from R. communis leaf on human cervical cancer (HeLa) cell line was studied. Results showed that the R. communis essential oil exhibited a moderate inhibitory effect on HeLa with IC50=2.63 mg/mL. The essential oil cytotoxicity of R. communis leaf was attributed to the presence of α-pinene (16.88 %) and to the synergetic effect between different compounds [94].

Rosmarinus officinalis L. (Lamiaceae)

The aerial part of R. officinalis essential oil was submitted to in vitro cytotoxicity bioassays against human cervical cancer (HeLa) cell line using the MTT assay based on cell viability. Results revealed that R. officinalis essential oil represented a higher cytotoxic activity with IC50=26.77 μg/mL. The cytotoxic activity of the R. officinalis essential oil attributed to its specific components [95]. Several terpenes are known for their antitumor attributes and their abundance in the essential oil, which contains a complex mixture of mono and sesquiterpenes, could presumably account for the cytotoxic activity of the R. officinalis essential oil, which might explain the synergism of active compounds with the other minor components involved in the process [225]. Kadri et al. [179] had mentioned that the main constituent of R. officinalis essential oil was 1,8-cineol (35.32 %), followed by trans-caryophyllene (14.47 %), borneol (9.37 %), camphor (8.97 %) and α-pinene (7.90 %). So, the cytotoxicity of the monoterpene 1,8-cineole was investigated against SK-OV-3, HO-8910 and Bel-7402 cell lines [182]. The sesquiterpene trans-caryophyllene extracted from Salvia officinalis exhibited a moderate cytotoxic effect against murine macrophage (RAW264.7) cells with IC50=90.5 µg/mL and human colon cancer (HCT-116) with IC50=145.8 µg/mL cell line [226]. Borneol, a monoterpenoid compound, had been used as a promoter of selenocysteine drug-induced apoptosis in human hepatocellular carcinoma (HepG2) cell line [227]. The cytotoxicity exhibited by the monoterpene α-pinene on a number of tumor cell lines was described to be comparable to those of anticancer agents, such as paclitaxel and mitomycin-C. Treatment with the monoterpenoid camphor prior to a radiation showed reduced growth of tumor volume [228].

Ruta chalpensis L. (Rutaceae)

The aqueous methanolic extract of R. chalpensis aerial part had a high anticancer activity against human bladder carcinoma (RT112), human laryngeal carcinoma (Hep2) and human myelogenous leukemia (K562) cell lines [23]. As regards the phytochemical composition of R. chalepensis extracts, Kacem et al. [108] had reported that it aerial part (leaf + stem) was characterized by the presence of six alkaloids (chaloridone, 8-methoxytaifine, graveoline, maculosidine, kokusaginine and arborinine), three coumarins (clausindin, chalepin and chalepensin) and three flavonoids (vicenin-2, rutin and isorhamnetin-3-O-rutinoside). Some of these compounds, namely graveoline, kokusaginine, arborinine chalepin and chalepensin, were isolated from R. angustifolia and they showed good cytotoxic effects against human lung carcinoma (A549) cell line [229].

Schinus molle L. (Anacardiaceae)

The essential oil of S. molle fruit was evaluated for its anticancer activity against human breast cancer cells (MCF-7). S. molle fruit essential oil was active against MCF7 with IC50=54 μg/mL. α-phellandrene (46.52 %), β-phellandrene (20.81 %), α-terpineol (8.38 %), α-pinene (4.34 %), β-pinene (4.96 %) and p-cymene (2.49 %) were the main compounds of S. molle fruit essential oil [96]. Among these compounds, α- and β-pinene showed cytotoxicity on tumor lymphocytes [230] and in others different tumor cell lines such as non-small-cell lung carcinoma [231], ovarian cancer and hepatocellular liver carcinoma [182]. Ferraz et al. [232] had investigated the cytotoxic effect of p-cymene in three tumor cell lines: HepG2, K562, and B16-F10 and they had proven the cytotoxic effect of p-cymene only in B16-F10 with IC50=20.06 µg/mL. α-terpineol showed significant cytotoxicity against Hep G2, a hepatocellular carcinomic human cell line; HeLa, an epithelioid carcinomic cell line; MOLT-4, a human lymphoblastic leukemia T cell line; K-562, a human chronic myelogenous leukemia cell line; and CTVR-1, an early B cell line from the bone marrow cells of a patient with acute myeloid leukemia [181].

Schinus terebinthifolius Raddi (Anacardiaceae)

The essential oil of S. terebinthifolius fruit was evaluated for its anticancer activity against human breast cancer (MCF-7) cells. S. terebinthifolius essential oil was efficient against tested cell lines with IC50=47 μg/mL. The chemical composition of S. terebinthifolius fruit essential oil was characterized by the presence of α-phellandrene (34.38 %), γ-cadinene (18.04 %), β-phellandrene (10.61 %), α-pinene (6.49 %), p-cymene (7.34 %), α-terpineol (5.60 %) and β-pinene (3.09 %). This essential oil demonstrated an appreciable cytotoxic effect which may be attributed by the presence of specific components such as the monoterpenes α-pinene, β-pinene, p-cymene and α-terpineol as well as the sesquiterpene γ-cadinene [96].

Silybum marianum L. (Asteraceae)

The antiproliferative activity of the individual flavonolignans (silychristin, silydianin and silybinin) and the oil seed extracts obtained from S. marianum by supercritical carbondioxide was evaluated against colon cancer (Caco-2) cells. Results showed that silychristin and silydianin did not exert a significant increase in antiproliferative properties. However, silybin and S. marianum oil seed extract showed a significant decrease in the proliferative activities [97]. In this line, Hogan et al. [233] also reported that silybin is the most active flavonolignan. S. marianum oil seed extract (IC50=70 µg/mL) exerted stronger cytotoxicity on Caco-2 than silybinin (IC50=96 µg/mL). Thus, although silybinin showed its potential cytotoxicity, some other active compounds may be responsible of the cytotoxicity of SC-CO2 extracts [97]. These results were consistent with those obtained by Hogan et al. [233], which presented a cytotoxic effect of silybin on other colon cancer (Fet, Geo and HCT116) cell lines.

Suaeda fruticosa Forssk (Chenopodiaceae)

The cytotoxicity of hexane, dichloromethane, methanol and water extracts from S. fruticosa shoot was evaluated against human skin fibroblast cell lines (WS1 and Detroit 551), colon carcinoma cell lines (DLD-1, Caco-2 and HT-29) and lung carcinoma cell line (A-549). Among the four solvent extracts, dichloromethane extract was most active against A-549 (IC50=49 µg/mL), DLD-1 (IC50=10 µg/mL), Caco-2 (IC50=140 µg/mL) and HT-29 (IC50=12 µg/mL). This data suggested that S. fruticosa had an influence on viability of cells and targets carcinoma colon cell lines mainly DLD-1. In addition, the four extracts were not found to be significantly cytotoxic against healthy human skin fibroblast cell lines WS1 and Detroit 551 [98]. To find S. fruticosa compounds responsible of the anticancer activity, Abbas et al. [234] had determined the phenolic profile of this plant which was characterized by the presence of flavonoids under form of quercetin, myricetin and Kaempferol. These three flavonoids were found to inhibit hepatocyte growth factor-induced medulloblastoma cell (children brain tumor) migration [235].

Teucrium pseudochamaepitys L. (Lamiaceae)

The toxicity in laryngeal carcinoma (Hep-2) cells was evaluated using the MTT assay for essential oil obtained from T. pseudochamaepitys aerial part. The IC50 of T. pseudochamaepitys essential oil on the cell line under examination was found to be 589.6 µg/mL [99]. In agreement with Prayong et al. [228], the essential oil of T. pseudochamaepitys aerial part was found to have moderate cytotoxicity against HEp-2 (100 µg/mL<IC50<1000 µg/mL). T. pseudochamaepitys essential oil was dominated by palmitic acid (26.1 %), apiole (7.1 %), caryophyllene oxide (6.3 %), myristicin (4.9 %), E-β-damascenone (4.6 %), α-cubebene (3.9 %), β-caryophyllene (3.5 %) and elemicin (3.3 %). Among these main constituents, apiole compound was found to inhibit the in vivo growth of human colon (COLO 205) cancer cells [236]. β-caryophyllene and caryophyllene oxide were proven to induce apoptosis in lymphoma and neuroblastoma cells [237]. For its role as anticancer agent, myristicin, found in Myristica fragrans Houtt, had cytotoxic and apoptotic effects in human cell line [238].

Teucrium ramosissimum L. (Lamiaceae)

The effects of the isolated flavonoids (genkwanin, cirsimaritin and 4ʹ,7-dimethoxy apigenin) and sesquiterpene (β-eudesmol) from T. ramosissimum leaf on inhibition of cell proliferation in human chronic myelogenous (K562) cells were examined using the MTT assay. Results showed that all these compounds had cytotoxic activity against K562. The strongest cytotoxic effect was obtained with β-eudesmol against K562 (IC50=20 µg/mL), followed by apigenin (IC50=30 µg/mL), 4ʹ,7-dimethoxy apigenin (IC50=30.25 µg/mL) and cirsimaritin (IC50=62.50 µg/mL). The IC50 value of genkwanin was 225 µg/mL [239]. In recent study, Sghaier et al. [100] had proven that β-eudesmol, isolated from T. ramosissimum leaf, may be a novel anticancer agent for the treatment of human lung (A549) and colon cancer (HT29 and Caco2) cell lines by different ways: by inhibition of superoxide production or by blocking proliferation, adhesion and migration.

Thymelaea hirsuta L. (Thymeleaceae)

To determine the antitumor activity of aqueous ethanol, hexane and water extracts from T. hirsuta aerial part against human adenocarcinoma (HT-29) cell line, cytotoxicity MTT assay was carried out. Results showed that all the extracts tested (hexane and ethanol-water) except the infusion extract also showed significant antitumor activity [101]. In this case, Kawano et al. [240] had demonstrated the antitumor effect of ethanol-water extracts and compounds like daphnanes isolated from this plant.

Tribulus terrestris L. (Zygophyllaceae)

The antitumor effects of T. terrestris different part fractions (fruit butanolic, fruit ethanolic, leaf aqueous hydrophilized, leaf butanolic and leaf ethanolic fractions) were assessed against tumor’s human ovarian cancer (IGROV) and human ovarian cancer (OVCAR) cell lines. Results showed that butanolic fraction exhibited the highest antiproliferative effect against IGROV and OVCAR cell lines toward total extract. OVCAR were rather sensitive to growth-inhibitory activity of leaf fractions while the IGROV were relatively sensitive of fruit fractions. The inhibition of proliferation tumor’s cell line of leaf butanolic fraction was twice as more effective against IGROV cell line (IC50=88.19 µg/mL) and four times more active toward OVCAR cell lines (IC50=94.76 µg/mL) than leaf aqueous lyophilized fraction with IC50=41.58 µg/mL for IGROV and IC50=25.22 µg/mL for OVGAR. Furthermore, the leaf butanolic fraction was rather more effective than leaf ethanolic fraction against both cell lines with IC50=25.44 µg/mL for IGROV and IC50=87.17 µg/mL for OVGAR. Leaf butanolic fraction with major compound hexamethylcyclotrisiloxane (30.92 %) exhibited the highest antiproliferative effect against ovary cancer. Such information may be useful effects and may be carcinogenic at high level of exposure [102].

Zygophyllum album Desf. (Zygophylaceae)

The cytotoxicity of hexane, dichloromethane and methanol extracts from Z. album aerial part was assessed against human colon carcinoma (DLD-1) and lung carcinoma (A-549) cell lines as well as health skin fibroblast (WS1) cell line. Result showed that among these three fractions, the dichloromethane extract was significantly active against the two carcinoma with IC50=37 µg/mL for A-549 and 48 µg/mL for DLD-1. These data suggested that Z. album had an influence on tumor cell viability and targeted colon and lung carcinoma cell lines, indicating the presence of powerful cytotoxic compounds in dichloromethane fraction. In addition, the last extract was not significantly cytotoxic against the healthy WS1 cells [103]. Z. album aerial part had an appreciable anti-tumor activity and might be considered as a potential source of anticancer compounds mainly triterpenoid saponins (zygophylosides K, G and F) and sterol (p-hydroxyphenethyl trans-ferulate) which were identified by Megdiche-Ksouri et al. [103]. In addition, Megdiche-Ksouri et al. [103] and Hussein et al. [241] had also noted the presence of flavonoids like quercetin and isorhamnetin derivatives. Or, isorhamnetin seems to be a chemotaxonomic marker in Zygophyllum genus [103] and it is a metabolite of quercetin which is known to reduce the risk of cancer [153].


To the best of our knowledge, this is the first review that summarizes several reports on the anticancer potential of Tunisian medicinal plants. Such information may be useful to the health professionals, scientists and scholars working in the field of pharmacology and therapeutics to produce new drug formulations to treat different types of cancer.


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About the article

Received: 2017-04-15

Accepted: 2017-06-06

Published Online: 2017-09-13

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design;in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Citation Information: Journal of Complementary and Integrative Medicine, Volume 15, Issue 1, 20170052, ISSN (Online) 1553-3840, DOI: https://doi.org/10.1515/jcim-2017-0052.

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