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Antimetabolite established as a successful therapeutics for advanced-stage breast cancers, but has recurrently shown to exhibit major side effects, which restrict drug therapy interventions. The most widely used chemotherapeutic agent is 5-Fluorouracil, however the recent report suggests that its antineoplastic activity is limited due to drug resistance developed by the cancer cells. The resistance results in the decrease in efficacy of 5-FU to improve either invasive disease-free survival or overall survival. In order to enhance 5-Fluorouracil mediated cytotoxicity, we have attempted the combination of the natural compound Naringin with 5-Fluorouracil. The combination of 5-Fluorouracil and Naringin inhibited the proliferation of MDA-MB-231 breast cancer cells determined using MTT assay. Importantly, combined treatment showed synergistic enhancement of breast cancer cell cytotoxicity. We next confirmed the cytotoxicity profile of the combination 5-Fluorouracil and Naringin in MDA-MB-231 breast cancer cells with trypan blue-based cell viability assay and determined that the IC50 value is 80 μM. When 5-Fluorouuracil and Naringin incubated there is a 7–10-fold increase in cytotoxic effect on breast cancer cells. These results demonstrates that application of naringin as an adjuvant treatment during 5-Fluorouracil administration might enhance the chemotherapeutic efficacy of 5-Fluorouracil.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer. 2010;127:2893-917.
Lu T, Gu M, Zhao Y, Zheng X, Xing C. Autophagy contributes to falcarindiol-induced cell death in breast cancer cells with enhanced endoplasmic reticulum stress. PloS One. 2017;12:e0176348.
Lambertini M, Goldrat O, Barragan-Carrillo R, Viglietti G, Demeestere I, Villarreal-Garza C. Viable options for fertility preservation in breast cancer patients: a focus on Latin America. Rev Invest Clin. 2017;69:103-13.
Ko BS, Noh WC, Kang SS, Park BW, Kang EY, Paik NS, et al. Changing patterns in the clinical characteristics of Korean breast cancer from 1996-2010 using an online nationwide breast cancer database. J Breast Cancer. 2012;15:393-400.
Althuis MD, Brogan DD, Coates RJ, Daling JR, Gammon MD, Malone KE, et al. Breast cancers among very young premenopausal women (United States). CCC. 2003;14:151-60.
Guo XF, Yang ZR, Wang J, Lei XF, Lv XG, Dong WG. Synergistic antitumor effect of puerarin combined with 5-fluorouracil on gastric carcinoma. Mol Med Rep. 2015;11: 2562-8.
Ferguson JE, Orlando RA. Curcumin reduces cytotoxicity of 5-Fluorouracil treatment in human breast cancer cells. J. Med. Food. 2015;18:497-502.
Cameron DA, Gabra H, Leonard RC. Continuous 5-fluorouracil in the treatment of breast cancer. Br J Cancer. 1994;70:120.
Curreri AR, Ansfield FJ, McIver FA, Waisman HA, Heidelberger C. Clinical studies with 5-fluorouracil. Cancer Res. 1958;18:478-84.
Li H, Yang B, Huang J, Xiang T, Yin X, Wan J, et al. Naringin inhibits growth potential of human triple-negative breast cancer cells by targeting β-catenin signaling pathway. Toxicol. Lett. 2013; 220:219-28.
Kanno SI, Tomizawa A, Hiura T, Osanai Y, Shouji A, Ujibe M, et al. Inhibitory effects of naringenin on tumor growth in human cancer cell lines and sarcoma S-180-implanted mice. Biol. Pharm. Bull. 2005;28:527-30.
Kim DI, Lee SJ, Lee SB, Park K, Kim WJ, Moon SK. Requirement for Ras/Raf/ERK pathway in naringin-induced G 1-cell-cycle arrest via p21WAF1 expression. Carcinogenesis. 2008;29:1701-9.
Siegelin MD, Reuss DE, Habel A, Herold-Mende C, von Deimling A. The flavonoid kaempferol sensitizes human glioma cells to TRAIL-mediated apoptosis by proteasomal degradation of survivin. Mol Cancer Ther. 2008;7:3566-74.
Bharti S, Rani N, Krishnamurthy B, Arya DS. Preclinical evidence for the pharmacological actions of naringin: a review. Planta med. 2014;80:437-51.
Chen R, Qi QL, Wang MT, Li QY. Therapeutic potential of naringin: an overview. Pharm. Biol. 2016;54:3203-10.
Choi EJ, Kim GH. 5-Fluorouracil combined with apigenin enhances anticancer activity through induction of apoptosis in human breast cancer MDA-MB-453 cells. Oncol. Rep. 2009;22:1533-7.
Gaballah HH, Gaber RA, Mohamed DA. Apigenin potentiates the antitumor activity of 5-FU on solid Ehrlich carcinoma: crosstalk between apoptotic and JNK-mediated autophagic cell death platforms. Toxicol. Appl. Pharmacol. 2017;316:27-35.
Kang Y, Hu W, Bai E, Zheng H, Liu Z, Wu J, et al. Curcumin sensitizes human gastric cancer cells to 5-fluorouracil through inhibition of the NFκB survival-signaling pathway. Onco Targets Ther. 2016;9: 7373.
Zhao L, Chen Z, Wang J, Yang L, Zhao Q, Wang J, et al. Synergistic effect of 5-fluorouracil and the flavanoid oroxylin A on HepG2 human hepatocellular carcinoma and on H 22 transplanted mice. Cancer Chemother. Pharmacol. 2010;65:481.
Ogasawara M, Matsubara T, Suzuki H. Screening of natural compounds for inhibitory activity on colon cancer cell migration. Biol Pharm Bull. 2001;24:720-3.
Strober W. Trypan blue exclusion test of cell viability. Curr Protoc Immunol. 2015; 111:A3-B.
Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003; 3:330.
Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, et al.Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil–leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000;18:136.
Douillard J, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355:1041-7.
Zhong ZF, Tan W, Tian K, Yu H, Qiang WA, Wang YT. Combined effects of furanodiene and doxorubicin on the migration and invasion of MDA-MB-231 breast cancer cells in vitro. Oncol. Rep. 2017;37:2016-24.
Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IκBα kinase and Akt activation. Mol Pharmacol. 2006;69:195-206.
Du B, Jiang L, Xia Q, Zhong L. Synergistic inhibitory effects of curcumin and 5-fluorouracil on the growth of the human colon cancer cell line HT-29. J CHEMOTHERAPY. 2006;52:23-8.
Meiyanto E, Hermawan A, Anindyajati A. Natural products for cancer-targeted therapy: Citrus flavonoids as potent chemopreventive agents. Asian Pac J Cancer Prev. 2012;13:427-36.
Cregan SP, Dawson VL, Slack RS. Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene. 2004;23:2785.
Ramesh E, Alshatwi AA. Naringin induces death receptor and mitochondria-mediated apoptosis in human cervical cancer (SiHa) cells. Food Chem Toxicol. 2013;51:97-105.
Lee WY, Hsu KF, Chiang TA, Chen CJ. Phellinus linteus extract induces autophagy and synergizes with 5-fluorouracil to inhibit breast cancer cell growth. Nutr. Cancer. 2015;67:275-84.
Lim SC, Choi JS. Effects of naringin on the pharmacokinetics of intravenous paclitaxel in rats. Biopharm Drug Dispos. 2006;27: 443-7.
R Prosperi J, H Goss K. A Wnt-ow of opportunity: Targeting the Wnt/β-catenin pathway in breast cancer. Curr Drug Targets. 2010;11:1074-88.
Han B, Jiang P, Liu W, Xu H, Li Y, Li Z, et al.Role of Daucosterol Linoleate on Breast Cancer: Studies on Apoptosis and Metastasis. J Agric Food Chem. 2018;66: 6031-41.
Gambi N, Tramontano F, Quesada P. Poly (ADPR) polymerase inhibition and apoptosis induction in cDDP-treated human carcinoma cell lines. Biochem Pharmacol. 2008;75:2356-63.
Mirzapur P, Khazaei MR, Moradi MT, Khazaei M. Apoptosis induction in human breast cancer cell lines by synergic effect of raloxifene and resveratrol through increasing proapoptotic genes. Life Sci. 2018;205:45-53.
Soldani C, Lazzè MC, Bottone MG, Tognon G, Biggiogera M, Pellicciari CE, et al. Poly (ADP-ribose) polymerase cleavage during apoptosis: when and where? Exp. Cell Res. 2001;269:193-201.
Fennell DA, Chacko A, Mutti L. BCL-2 family regulation by the 20S proteasome inhibitor bortezomib. Oncogene. 2008;27: 1189.
Shen ZT, Wu XH, Wang L, Li B, Zhu XX. Effects of gemcitabine on radiosensitization, apoptosis, and Bcl-2 and Bax protein expression in human pancreatic cancer xenografts in nude mice. Genet Mol Res. 2015;14:15587- 96.
Cekanova M, Fernando RI, Siriwardhana N, Sukhthankar M, de la Parra C, Woraratphoka J, et al.BCL-2 family protein, BAD is down-regulated in breast cancer and inhibits cell invasion. Exp. Cell Res. 2015;331:1-0.
Al-Bazz YO, Underwood JC, Brown BL, Dobson PR. Prognostic significance of Akt, phospho-Akt and BAD expression in primary breast cancer. Eur. J. Cancer. 2009;45:694-704.
Lazer LM, Sadhasivam B, Palaniyandi K, Muthuswamy T, Ramachandran I, Balakrishnan A, et al. Chitosan-based nano-formulation enhances the anticancer efficacy of hesperetin. Int J Biol Macromol. 2018;107:1988-98.