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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

CiteScore 2017: 1.41

SCImago Journal Rank (SJR) 2017: 0.472
Source Normalized Impact per Paper (SNIP) 2017: 0.564

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Inhibition of AKT signaling by supercritical CO2 extract of mango ginger (Curcuma amada Roxb.) in human glioblastoma cells

Cheppail Ramachandran / Gilda Portalatin / Karl-W Quirin / Enrique Escalon / Ziad Khatib / Steven J. Melnick
Published Online: 2015-10-06 | DOI: https://doi.org/10.1515/jcim-2015-0005


Background: Mango ginger (Curcuma amada Roxb.) is a less-investigated herb for anticancer properties than other related Curcuma species. AKT (a serine/threonine protein kinase B, originally identified as an oncogene in the transforming retrovirus AKT8) plays a central role in the development and promotion of cancer. In this investigation, we have analyzed the effect of supercritical CO2 extract of mango ginger (CA) on the genetic pathways associated with AKT signaling in human glioblastoma cells.

Methods: The inhibitory effect of supercritical CO2 extract of mango ginger (Curcuma amada) on AKT signaling was investigated in U-87MG glioblastoma cells.

Results: CA was highly cytotoxic to glioblastoma cell line (IC50=4.92±0.81 µg/mL) compared to mHypoE-N1 normal mouse hypothalamus cell line (IC50=40.57±0.06 µg/mL). CA inhibits AKT (protein Kinase B) and adenosine monophophate -activated protein kinase α (AMPKα) phosphorylation significantly in a dose-dependent manner. The cell migration which is necessary for invasion and metastasis was also inhibited by CA treatment, with about 43% reduction at 20 µg/mL concentration. Analysis of mRNA and protein expression of genes associated with apoptosis, cell proliferation and angiogenesis showed that CA modulates expression of genes associated with apoptosis (Bax, Bcl-2, Bcl-X, BNIP3, caspase-3, mutant p53 and p21), cell proliferation (Ki67) and angiogenesis vascular endothelial growth factor (VEGF). Additionally, heat shock protein 90 (HSP90) and AMPKα genes interacting with the AKT signaling pathway were also downregulated by CA treatment.

Conclusions: These results indicate the molecular targets and mechanisms underlying the anticancer effect of CA in human glioblastoma cells.

Keywords: AKT signaling; cell migration; gene expression; glioblastoma; mango ginger


  • 1. Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 2005;93:29–86.Google Scholar

  • 2. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.Web of ScienceGoogle Scholar

  • 3. Sun M, Yang L, Feldman RI, Sun XM, Bhalla KN, Jove R, et al. Activation of phosphatidylinositol 3-kinase/Akt pathway by androgen through interaction of P85alpha, androgen receptor, and Src. J Biol Chem 2003;278:42992–3000.Google Scholar

  • 4. Art A, Gears A, Muerkoster S, Vorndamm J, Kruse ML, Folsch UR, et al. Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene 2003;22:3243–51.Google Scholar

  • 5. Cheng JQ, Jiang X, Fraser M, Li M, Dan HC, Sun M, et al. Role of X-linked inhibitor of apoptosis protein in chemoresistance in ovarian cancer: possible involvement of the phosphoinositide-3 kinase/Akt pathway. Drug Resist Updat 2002;5:131–46.PubMedGoogle Scholar

  • 6. Falasca M. P3K/Akt signaling pathway specific inhibitors: a novel strategy to sensitize cancer cells to anti-cancer drugs. Curr Pharm Des 2010;16:1410–116.Google Scholar

  • 7. Knuefermann C, Lu Y, Liu B, Jin W, Liang K, Wu L, et al. HER2/PI-3k/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene 2003;22:3205–12.Google Scholar

  • 8. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004;16:117–27.Google Scholar

  • 9. Leevers SJ, Vanhaesebroeck B, Waterfield MD. Signaling through phosphoinositde-3-kinases: the lipids take center stage. Curr Opin Cell Biol 1999;11:219–25.Google Scholar

  • 10. Woodgett JR. Recent advances in the protein kinase B signaling pathway. Curr Opin Cell Biol 2005;17:150–7.Google Scholar

  • 11. Whang YE, Yuan XJ, Liu Y, Majumder S, Lewis TD. Regulation of sensitivity to TRAIL by the PTEN tumor suppressor. Vitam Horm 2004;67:409–26.Google Scholar

  • 12. Downward J. PI 3 kinase, Akt and cell survival. Semin Cell Dev Biol 2004;15:177–82.Google Scholar

  • 13. Mayo LD, Donner DB. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem Sci 2002;27:462–7.Google Scholar

  • 14. Zhou BP, Hung MC. Novel targets of Akt, P21(Cipl/WAF1), and MDM2. Semin Oncol 2002;29:62–70.Google Scholar

  • 15. Hussain A, Virmani O, Popli SP, Misra LN, Gupta MM. Dictionary of Indian medicinal plants, vol. 2. Lucknow: Central Institute of Medicinal and Aromatic Plants, 1992:39.

  • 16. Kirtikar KR, Basu BD. Indian medicinal plants, vol. 4, 2nd ed. Dehradun: Bishen Singh Mahendra Pal Singh, 1984;2422–3.Google Scholar

  • 17. Warrier PK, Nambiar VP, Ramankutty C. Indian medicinal plants – a compendium of 500 species, vol. 1. Chennai: Orient Longman Pvt. Ltd., 1994:106.Google Scholar

  • 18. Ramachandran C, Quirin K-W, Escalon E, Lollett IV, Melnick SJ. Therapeutic effect of supercritical CO2 extracts of Curcuma species with cancer drugs in rhabdomyosarcoma cell lines. Phytother Res 2015.DOI:10.1002/ptr5360.Web of ScienceCrossref

  • 19. Ramachandran C, Lollett IV, Escalon E, Quirin K-W, Melnick SJ. Anticancer potential and mechanism of mango ginger (Curcuma amada Roxb.) supercritical CO2 extract in human glioblastoma cells. J Evid Based Complement Altern Med 2015;20:109–19.Google Scholar

  • 20. Gonzalez MA, Mancebo-Aracil J, Tangarife-Castano V, Agudelo-Gomez L, Zapata B, Mesa-Arango A, et al. Synthesis and biological evaluation of (+)-labdadienedial, derivatives and precursors from (+)-sclareolide. Eur J Med Chem 2010;45:4403–8.Google Scholar

  • 21. Jambunathan S, Bangarusamy D, Padma PR, Sundaravadivelu S. Cytotoxic activity of the methanolic extract of leaves and rhizomes of Curcuma amada Roxb against breast cancer cell lines. Asian Pac J Trop Med 2014;7 Suppl1:S405–9.Google Scholar

  • 22. Malek SN, Lee GS, Hong SL, Yaacob H, Wahab NA, Weber HF, et al. Phytochemical and cytotoxic investigations of Curcuma mangga rhizomes. Molecules 2011;16:4539–48.Web of ScienceGoogle Scholar

  • 23. Samant LR. Curcuma amada Roxb.: a phytopathological review. J Pharm Res 2012;5:1992–3.Google Scholar

  • 24. Guruvayoorappan C, Kuttan G. Amentoflavone inhibits experimental tumor metastasis through a regulatory mechanism involving MMP 2, MMP 9, prolyl hydroxylase, lysyl oxidase, VEGF, ERK 1, ERK 2, STAT 1, NM23 and cytokines in lung tissues of C57BL/6 mice. Immunopharmacol Immunotoxicol 2008;30:711–27.Google Scholar

  • 25. Liu KC, Huang AC, Wu PP, Lin HY, Cheh FS, Yang JS, et al. Gallic acid suppresses the migration and invasion of PC 3 human prostate cancer cells via inhibition of matrix metalloproteinase 2 and 9 signaling pathways. Oncol Rep 2011;26:177–84.Google Scholar

  • 26. Suzuki T, Bridges D, Nakada d, Skiniotis G, Morrison SJ, Lin J, et al. Inhibition of AMPK catabolic action by GSK3. Mol Cell 2013;50:407–10.Web of ScienceGoogle Scholar

  • 27. Cochrane CB, Nair PK, Melnick SJ, Resek AP, Ramachandran C. Anticancer effects of Annona glabra plant extracts in human leukemia cell lines. Anticancer Res 2008;28:965–72.Google Scholar

  • 28. Gross A, Yin XM, Wang K, Wei MC, Jockel J, Millman C, et al. Caspase cleaved BID targets mitochondria and is required for Cytochrome C release, while Bcl-Xl prevents this release but not tumor necrosis factor-R1/Fas death. J Biol Chem 1999;27:1156–63.Google Scholar

  • 29. Schafer KA. The cell cycle: a review. Vet Pathol 1998;35:461–78.Google Scholar

  • 30. Mitsuuchi Y, Johnson SW, Selvakumaran M, Williams SJ, Hamilton TC, Testa JR. The phosphatidylinositol 3-kinase/AKT signal transduction pathway plays a critical role in the pression of p21WAF1/CIPI/SD11 induced by cisplatin and Paclitaxel. Cancer Res 2000;60:5390–4.Google Scholar

  • 31. Park WH, Geol JG, Kim ES, Hyun JM, Jng CW, Lee CC, et al. Arsenic trioxide-mediated growth inhibition in MC/CAR myeloma cells via cell cycle arrest in association with induction of cyclin-dependent kinase inhibitor, P21, and apoptosis. Cancer Res 2000;60:3065–71.Google Scholar

  • 32. Wang X, Chen JX, Liu YH, You C, Mao Q. Mutant TP53 enhances the resistance of glioblastoma cells to temozolomide by up-regulating O(6)-methylguanine DNA-methyltransferase. Neurol Sci 2013;34:1421–8.Web of ScienceGoogle Scholar

  • 33. Motoshima H, Goldstein BJ, Igata M, Araki E. AMPK and cell proliferation – AMPK as a therapeutic target for atheroscleorosis and cancer. J Physiol 2006;574:63–71.Google Scholar

  • 34. Liang MA, Sato F, Sato R, Matsubara T, Hirai K, Yamasaki M, et al. Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer. Oncol Rep 2014;31:2482–92.Google Scholar

  • 35. Taniguchi H, Hasegawa H, Sasaki d, Ando K, Sawayama Y, Imanishi D, et al. Heat shock protein 90 inhibitor NVP-AUY922 exerts potent activity against adult T-cell leukemia-lymphoma cells. Cancer Sci 2014. DOI:10.1111/cas/12540.

About the article

Received: 2015-02-01

Accepted: 2015-07-15

Published Online: 2015-10-06

Published in Print: 2015-12-01

Citation Information: Journal of Complementary and Integrative Medicine, Volume 12, Issue 4, Pages 307–315, ISSN (Online) 1553-3840, ISSN (Print) 2194-6329, DOI: https://doi.org/10.1515/jcim-2015-0005.

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