nhibitory effect of gemcitabine and brucine on MDA MB-231human breast cancer cells
Keywords:
Brucine, Gemcitabine, MDA MB-231, p65, in vitro scratch assayAbstract
Combination of natural compounds and cytotoxic drugs represents a logical therapeutic approach for breast cancer. Brucine, a natural plant alkaloid is reported to possess cytotoxic, antiinflammatory and anti-cancer activities. Gemcitabine is a nucleoside analog, commonly used in the treatment of several solid tumors, including breast cancer. In the present study we have examined the anticancer effect of brucine and gemcitabine on MDA MB-231 human breast cancer cells. Cell proliferation was assessed using MTT assay. Soft agar assay was used to evaluate the in-vitro clonogencity of MDA MB-231 cells. Cell migration was determined by in-vitro scratch assay and expression of p65 (NF-kB subunit) was evaluated by western blot analysis. Combination treatment with brucine and gemcitabine resulted in a significant inhibition of cell proliferation than either brucine or gemcitabine alone. Cells treated with combination of brucine and gemcitabine showed additive inhibition in colony formation and cell migration than treated with individual agents. The cells treated with brucine at 300 øM showed a significant decrease in p65-NF-kB expression but in combination treatment there was no additive inhibition of p65 expression compared to brucine treated cells. Overall, our results suggested that brucine in combination with gemcitabine showed supra-additive anticancer effects in MDA MB-231 cells and warrants further in-vivo studies in experimental animal models.
References
. Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin. 1999; 49(1): 33- 64.
. Coughlin S S, Ekwueme D U. Breast cancer as a global health concern. Cancer Epidemiology 2009;33(5): 315-318.
. Heinemann V. Gemcitabine in metastatic breast cancer. Exp. Rev. Anticancer Ther
;5(3):429-443.
. Cragg GM, Newman DJ. Plants as a source of anticancer agents. J Ethopharmacol 2005;100(1-2):72-79.
. Berkovich L, Ron I, Earon G, Abu-Ghanem S, Rimmon A, Lev-Ari S. The role of medicinal herbs with anti-inflammatory properties in prevention and treatment of cancer. Harefuah 2012;151(11): 629-632.
. Behpour M, Ghoreishi SM, Khayatkashani M, Motaghedifard M. A new method for the simultaneous analysis of strychnine and brucine in Strychnos nux-vomica unprocessed and processed seeds using a carbon-paste electrodemodified with multi-walled carbon nanotubes. Phytochem Anal 2012;23(2):95-102.
. Agrawal SS, Saraswati S, Mathur R, Pandey M. Cytotoxic and antitumor effects of brucine on ehrlich ascites tumor and human cell line. Life Sci 2011;89(5-6):147-58.
. Cai BC, Wang TS, Kurokawa M, Shiraki K, Hattori M. Cytotoxicities of alkaloids from processed and unprocessed seeds of Strychnos nux-vomica, Acta Pharm Sinic 1998;19(5):425-28.
. Deng XK, Yin W, Li WD, Yin FZ, Lu XY, Zhang XC, Hua ZC, Cai BC.The anti-tumor effects of alkaloids from the seeds of Strychnos nux vomica on HepG2 cells and its possible mechanism, J Ethnopharmacol 2006;106(2):179-86.
. Yin W, Deng XK, Yin FZ, Zhang XC, Cai BC. The cytotoxicity induced by brucine from the seed of Strychnos nux-vomica proceeds via apop¬tosis and is mediated by cyclooxygenase-2 and Caspase-3 in SMMC 7721 cells. Food Chem Toxicol 2007; 45(9):1700-08.
. Rao PS, Ramanadham M, Prasad MN. Anti-proliferative and cytotoxic effects of Strychnos nux-vomica root extract on human multiple myeloma cell line-RPMI 8226. Food Chem Toxicol 2009;47(2):283-88.
. Zheng L, Wang X, Luo W, Zhan Y, Zhang Y. Brucine, an effective natural compound derived from nux-vomica, induces G1 phase arrest and apoptosis in LoVo cells. Food and Chem Toxicolo 2013;58:332-39.
. Chen J, Wang X, Qu YG, Chen ZP, Cai H, Liu X, Xu F, Lu TL, Cai BC. Analgesic and anti-inflammatory activity and pharmacokinetics of alkaloids from seeds of Strychnos nux-vomica after trans dermal administration: effect of changes in alkaloid composition. Journal of Ethno pharmacolo 2012;139(1):181-88.
. Baud V, Karin M. Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov 2009;8(1):33-40.
. Ramachandran C, Resek A, Esclon E, Aviram A, Melmick S. Potention of gemcitabine by tumeric force in pancreatic cancer cell lines. Oncology Reports 2010; 23(6):1529-1535.
. Ramalingam S, Belani C. Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions. Oncologist 2008;13 (suppl 1):5-13.
. Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor- kB-regulated gene products. Cancer Res 2007; 67:3853-61.
. Tharakan ST, Inamoto T, Sung B, Aggarwal BB, Kamat AM. Curcumin potentiates the antitumor effects of gemcitabine in an orthotopic model of human bladder cancer through suppression of proliferative and angiogenic biomarkers. Bioc Pharmacol 2010; 79(2): 218-28.
. Biswas DK, Shi Q, Baily S, Strickland I, Ghosh S, Pardee AB, Iglehart JD. NF-kappa B activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proc Natl Acad Sci U S A 2004; 101(27):10137-42.
. Zhu G, Yin F, Deng X. Effect of NF-kappaB on inhibition of non-small cell lung cancer cell cyclooxygenase-2 by brucine. Zhongguo Zhong Yao Za Zhi 2012; 37(9):1269-73.
. Zheng L, He X, Ma W, Dai B, Zhan Y, Zhang Y. Ta1722, an antiangiogenesis inhibitor targeted on VEGFR-2 against human hepatoma. Biomed Pharmacother 2011; 66(7):499-05.
. Keane MM, Ettenberg SA, Nau MM, Russell EK, Lipkowitz S. Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. Cancer Res 1999;59:734-41.
. Shu G, Mi X, Cai J, Zhang X, Yin W, Yang X, Li Y, Chen L, Deng X. Brucine, an alkaloid from seeds of Strychnos nux-vomica Linn, represses hepatocellular carcinoma cell migration and metastasis: The role of hypoxia inducible factor 1 pathway. Toxicol Lett 2013; 222(2): 91-101.
. Lai HW, Chien SY, Kuo SJ, Tseng LM, Lin HY, Chi CW, Chen DR. The Potential utility of curcumin in the treatment of HER-2-Overexpressed breast cancer: An in vitro and in vivo comparison study with Herceptin. Evid Based Complement Alternat Med 2012;10:486568.
. Cheah YH, Nordin FJ, Sarip R, Tee TT, Azimahtol HL, Sirat HM, Rashid BA, Abdullah NR, Ismail Z. Combined xanthorrhizol-curcumin exhibits synergistic growth inhibitory activity via apoptosis induction in human breast cancer cells MDA-MB-231. Cancer Cell Int 2009; 2:9-1.
. Deng X, Yin F, Lu X, Cai B, Yin W. The apoptotic effect of brucine from the seed of Strychnos nux-vomica on human hepatoma cells is mediated via Bcl-2 and Ca2+ involved mitochondrial pathway. Tox Sci 2006; 91(1):59-69.