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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

Gamma-Tocotrienol Synergistically Promotes the Anti-proliferative and Pro-apoptotic Effects of Etoposide on Breast Cancer Cell Lines

Author(s): Maya Idriss, Maria Younes, Sonia Abou Najem, Mohammad Hassan Hodroj, Rajaa Fakhoury and Sandra Rizk*

Volume 15, Issue 7, 2022

Published on: 10 May, 2022

Article ID: e310122200713 Pages: 7

DOI: 10.2174/1874467215666220131095611

Price: $65

Abstract

Background: Breast Cancer is one of the most commonly diagnosed cancers worldwide and a major cause of death among women. Although chemotherapeutic agents remain the keystones in cancer therapy, significant side effects have failed to provide a safe and tolerable treatment for cancer patients. Dietary antioxidant vitamins were extensively investigated over the past years and their relevance in cancer chemotherapy remains to be elucidated.

Objective: In the current study, we aimed to investigate the anti-proliferative and apoptotic effects of combining γ-tocotrienol, a member of the vitamin E family, with the chemotherapeutic drug etoposide in MCF-7 and MDA-MB-231 breast cancer cell lines.

Methods: The antiproliferative effect of etoposide combined with γ-tocotrienol was measured using MTS viability reagent. The pro-apoptotic effect was elucidated through Cell Death ELISA and dual Annexin V/PI staining followed by flow cytometric analysis.

Results: Our results showed that etoposide significantly decreased the cell growth of both cell lines, with MDA-MB-231 cells being more sensitive to etoposide treatment than MCF-7. Moreover, simultaneous treatment of both breast cancer cell lines with low doses of γ-tocotrienol and etoposide induced a synergistic antiproliferative effect (CI<1). Furthermore, the combination therapy significantly increased the percentage of total apoptotic cells in the MDA-MB-231 cell line and the degree of DNA fragmentation as compared to treatment with either compound alone.

Conclusion: In conclusion, our results provide evidence for the profound anti-tumorigenic effect of combined etoposide and γ-tocotrienol in the breast cancer cell lines.

Keywords: Apoptosis, combination therapy, chemotherapeutic drugs, gamma-tocotrienol, mammary carcinoma, vitamin E derivatives.

Graphical Abstract

[1]
Anastasiadi, Z.; Lianos, G.D.; Ignatiadou, E.; Harissis, H.V.; Mitsis, M. Breast cancer in young women: an overview. Updates Surg., 2017, 69(3), 313-317.
[http://dx.doi.org/10.1007/s13304-017-0424-1] [PMID: 28260181]
[2]
Tao, Z.; Shi, A.; Lu, C.; Song, T.; Zhang, Z. Zhao, J. Breast Cancer: Epidemiology and etiology. Cell Biochem. Biophys., 2015, 72(2), 333-338.
[http://dx.doi.org/10.1007/s12013-014-0459-6] [PMID: 25543329]
[3]
Noel, B.; Singh, S.K.; Lillard, J.W.; Singh, R. Role of natural compounds in preventing and treating breast cancer. Front. Biosci. (Schol. Ed.), 2020, 12, 137-160.
[http://dx.doi.org/10.2741/S544] [PMID: 32114452]
[4]
Peh, H.Y.; Tan, W.S.D.; Liao, W.; Wong, W.S.F. Vitamin E therapy beyond cancer: Tocopherol versus tocotrienol. Pharmacol. Ther., 2016, 162, 152-169.
[http://dx.doi.org/10.1016/j.pharmthera.2015.12.003] [PMID: 26706242]
[5]
Ahmed, R.A.; Alawin, O.A.; Sylvester, P.W. γ-Tocotrienol reversal of epithelial-to-mesenchymal transition in human breast cancer cells is associated with inhibition of canonical Wnt signalling. Cell Prolif., 2016, 49(4), 460-470.
[http://dx.doi.org/10.1111/cpr.12270] [PMID: 27323693]
[6]
Liu, H-K.; Wang, Q.; Li, Y.; Sun, W-G.; Liu, J-R.; Yang, Y-M.; Xu, W.L.; Sun, X.R.; Chen, B.Q. Inhibitory effects of gamma-tocotrienol on invasion and metastasis of human gastric adenocarcinoma SGC-7901 cells. J. Nutr. Biochem., 2010, 21(3), 206-213.
[http://dx.doi.org/10.1016/j.jnutbio.2008.11.004] [PMID: 19195866]
[7]
Sylvester, P.W.; McIntyre, B.S.; Gapor, A.; Briski, K.P. Vitamin E inhibition of normal mammary epithelial cell growth is associated with a reduction in protein kinase C(alpha) activation. Cell Prolif., 2001, 34(6), 347-357.
[http://dx.doi.org/10.1046/j.1365-2184.2001.00221.x] [PMID: 11736999]
[8]
Xu, W.; Mi, Y.; He, P.; He, S.; Niu, L. γ-Tocotrienol inhibits proliferation and induces apoptosis via the mitochondrial pathway in human cervical cancer HeLa cells. Molecules, 2017, 22(8), 1299.
[http://dx.doi.org/10.3390/molecules22081299] [PMID: 28777347]
[9]
Hsieh, T-C.; Elangovan, S.; Wu, J.M. gamma-Tocotrienol controls proliferation, modulates expression of cell cycle regulatory proteins and up-regulates quinone reductase NQO2 in MCF-7 breast cancer cells. Anticancer Res., 2010, 30(7), 2869-2874.
[PMID: 20683025]
[10]
Pierpaoli, E.; Viola, V.; Pilolli, F.; Piroddi, M.; Galli, F.; Provinciali, M. Gamma- and delta-tocotrienols exert a more potent anticancer effect than alpha-tocopheryl succinate on breast cancer cell lines irrespective of HER-2/neu expression. Life Sci., 2010, 86(17-18), 668-675.
[http://dx.doi.org/10.1016/j.lfs.2010.02.018] [PMID: 20188744]
[11]
Yap, W.N.; Zaiden, N.; Tan, Y.L.; Ngoh, C.P.; Zhang, X.W.; Wong, Y.C.; Ling, M.T.; Yap, Y.L. Id1, inhibitor of differentiation, is a key protein mediating anti-tumor responses of gamma-tocotrienol in breast cancer cells. Cancer Lett., 2010, 291(2), 187-199.
[http://dx.doi.org/10.1016/j.canlet.2009.10.012] [PMID: 19926394]
[12]
Martin, B.; Seguin, J.; Annereau, M.; Fleury, T.; Lai-Kuen, R.; Neri, G.; Lam, A.; Bally, M.; Mignet, N.; Corvis, Y. Preparation of parenteral nanocrystal suspensions of etoposide from the excipient free dry state of the drug to enhance in vivo antitumoral properties. Sci. Rep., 2020, 10(1), 18059.
[http://dx.doi.org/10.1038/s41598-020-74809-z] [PMID: 33093456]
[13]
Nitiss, J.L. Targeting DNA topoisomerase II in cancer chemotherapy. Nat. Rev. Cancer, 2009, 9(5), 338-350.
[http://dx.doi.org/10.1038/nrc2607] [PMID: 19377506]
[14]
Zhang, X.; Hofmann, S.; Harbeck, N.; Jeschke, U.; Sixou, S. Impact of etoposide on BRCA1 expression in various breast cancer cell lines. Drugs R D., 2017, 17(4), 569-583.
[http://dx.doi.org/10.1007/s40268-017-0208-6] [PMID: 28879638]
[15]
Hainsworth, J.D.; Greco, F.A. Etoposide: Twenty years later. Ann. Oncol., 1995, 6(4), 325-341.
[http://dx.doi.org/10.1093/oxfordjournals.annonc.a059180] [PMID: 7619747]
[16]
Younes, M.; Ammoury, C.; Haykal, T.; Nasr, L.; Sarkis, R.; Rizk, S. The selective anti-proliferative and pro-apoptotic effect of A. cherimola on MDA-MB-231 breast cancer cell line. BMC Complement Med Ther, 2020, 20(1), 343.
[http://dx.doi.org/10.1186/s12906-020-03120-1] [PMID: 33187495]
[17]
Montecucco, A.; Biamonti, G. Cellular response to etoposide treatment. Cancer Lett., 2007, 252(1), 9-18.
[http://dx.doi.org/10.1016/j.canlet.2006.11.005] [PMID: 17166655]
[18]
Chen, L.; Cui, H.; Fang, J.; Deng, H.; Kuang, P.; Guo, H.; Wang, X.; Zhao, L. Glutamine deprivation plus BPTES alters etoposide- and cisplatin-induced apoptosis in triple negative breast cancer cells. Oncotarget, 2016, 7(34), 54691-54701.
[http://dx.doi.org/10.18632/oncotarget.10579] [PMID: 27419628]
[19]
Idriss, M.; Hodroj, M.H.; Fakhoury, R.; Rizk, S. Beta-tocotrienol exhibits more cytotoxic effects than gamma-tocotrienol on breast cancer cells by promoting apoptosis via a P53-independent PI3-kinase dependent pathway. Biomolecules, 2020, 10(4), 577.
[http://dx.doi.org/10.3390/biom10040577] [PMID: 32283796]
[20]
Nesaretnam, K.; Stephen, R.; Dils, R.; Darbre, P. Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status. Lipids, 1998, 33(5), 461-469.
[http://dx.doi.org/10.1007/s11745-998-0229-3] [PMID: 9625593]
[21]
Nesaretnam, K.; Guthrie, N.; Chambers, A.F.; Carroll, K.K. Effect of tocotrienols on the growth of a human breast cancer cell line in culture. Lipids, 1995, 30(12), 1139-1143.
[http://dx.doi.org/10.1007/BF02536615] [PMID: 8614304]
[22]
Kagan, V.E.; Kuzmenko, A.I.; Tyurina, Y.Y.; Shvedova, A.A.; Matsura, T.; Yalowich, J.C. Pro-oxidant and antioxidant mechanisms of etoposide in HL-60 cells: Role of myeloperoxidase. Cancer Res., 2001, 61(21), 7777-7784.
[PMID: 11691792]
[23]
Chou, T-C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev., 2006, 58(3), 621-681.
[http://dx.doi.org/10.1124/pr.58.3.10] [PMID: 16968952]
[24]
Singh, K.; Bhori, M.; Kasu, Y.A.; Bhat, G.; Marar, T. Antioxidants as precision weapons in war against cancer chemotherapy induced toxicity - exploring the armoury of obscurity. Saudi Pharm. J., 2018, 26(2), 177-190.
[http://dx.doi.org/10.1016/j.jsps.2017.12.013] [PMID: 30166914]
[25]
Park, S.K.; Sanders, B.G.; Kline, K. Tocotrienols induce apoptosis in breast cancer cell lines via an endoplasmic reticulum stress-dependent increase in extrinsic death receptor signaling. Breast Cancer Res. Treat., 2010, 124(2), 361-375.
[http://dx.doi.org/10.1007/s10549-010-0786-2] [PMID: 20157774]
[26]
Shacter, E.; Williams, J.A.; Hinson, R.M.; Sentürker, S.; Lee, Y.J. Oxidative stress interferes with cancer chemotherapy: Inhibition of lymphoma cell apoptosis and phagocytosis. Blood, 2000, 96(1), 307-313.
[http://dx.doi.org/10.1182/blood.V96.1.307] [PMID: 10891466]
[27]
Shirode, A.B.; Sylvester, P.W. Mechanisms mediating the synergistic anticancer effects of combined γ-tocotrienol and celecoxib treatment. J. Bioanal. Biomed., 2011, 3, 001-0007.
[http://dx.doi.org/10.4172/1948-593X.1000036] [PMID: 22140606]
[28]
Shirode, A.B.; Sylvester, P.W. Synergistic anticancer effects of combined γ-tocotrienol and celecoxib treatment are associated with suppression in Akt and NFkappaB signaling. Biomed. Pharmacother., 2010, 64(5), 327-332.
[http://dx.doi.org/10.1016/j.biopha.2009.09.018] [PMID: 19954924]
[29]
Montecucco, A.; Zanetta, F.; Biamonti, G. Molecular mechanisms of etoposide. EXCLI J., 2015, 14, 95-108.
[http://dx.doi.org/10.17179/excli2015-561] [PMID: 26600742]
[30]
Chandra, D.; Choy, G.; Deng, X.; Bhatia, B.; Daniel, P.; Tang, D.G. Association of active caspase 8 with the mitochondrial membrane during apoptosis: Potential roles in cleaving BAP31 and caspase 3 and mediating mitochondrion-endoplasmic reticulum cross talk in etoposide-induced cell death. Mol. Cell. Biol., 2004, 24(15), 6592-6607.
[http://dx.doi.org/10.1128/MCB.24.15.6592-6607.2004] [PMID: 15254227]
[31]
Dronamraju, V.; Ibrahim, B.A.; Briski, K.P.; Sylvester, P.W. γ-Tocotrienol suppression of the Warburg effect is mediated by AMPK activation in human breast cancer cells. Nutr. Cancer, 2019, 71(7), 1214-1228.
[http://dx.doi.org/10.1080/01635581.2019.1599969] [PMID: 30955359]
[32]
Parajuli, P.; Tiwari, R.V.; Sylvester, P.W. Anticancer effects of γ-Tocotrienol are associated with a suppression in aerobic glycolysis. Biol. Pharm. Bull., 2015, 38(9), 1352-1360.
[http://dx.doi.org/10.1248/bpb.b15-00306] [PMID: 26328490]
[33]
Takahashi, K.; Loo, G. Disruption of mitochondria during tocotrienol-induced apoptosis in MDA-MB-231 human breast cancer cells. Biochem. Pharmacol., 2004, 67(2), 315-324.
[http://dx.doi.org/10.1016/j.bcp.2003.07.015] [PMID: 14698044]
[34]
Daugas, E.; Susin, S.A.; Zamzami, N.; Ferri, K.F.; Irinopoulou, T.; Larochette, N.; Prévost, M.C.; Leber, B.; Andrews, D.; Penninger, J.; Kroemer, G. Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J., 2000, 14(5), 729-739.
[http://dx.doi.org/10.1096/fasebj.14.5.729] [PMID: 10744629]
[35]
Loganathan, R.; Selvaduray, K.R.; Nesaretnam, K.; Radhakrishnan, A.K. Tocotrienols promote apoptosis in human breast cancer cells by inducing poly(ADP-ribose) polymerase cleavage and inhibiting nuclear factor kappa-B activity. Cell Prolif., 2013, 46(2), 203-213.
[http://dx.doi.org/10.1111/cpr.12014] [PMID: 23510475]
[36]
Nesaretnam, K.; Meganathan, P.; Veerasenan, S.D.; Selvaduray, K.R. Tocotrienols and breast cancer: the evidence to date. Genes Nutr., 2012, 7(1), 3-9.
[http://dx.doi.org/10.1007/s12263-011-0224-z] [PMID: 21516480]

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