Abstract
Aims: To investigate the effect of methotrexate and soy isoflavones genistein and daidzein on MDA-MB-231 breast cancer cell viability. Study Design: In-vitro study using cultured cellsPlace and Duration of Study: Nutrition Innovations Centre for Food & Health (NICHE), School of Biomedical Sciences, Ulster University, data collected September 2014-2015.Methods: Human breast cancer MDA-MB-231 cells were cultured in DMEM (with 10% FBS, 1% Pen strep) and treated with methotrexate, genistein or daidzein for 72 hrs. Combinations treatments used non-fixed ratios of methotrexate (0-100 μM) and genistein or daidzein (30 μM) with cell viability monitored using the MTT assay. Results: The 50% effect dose (EC50) was 44.7±6.4 μM for methotrexate, 55.8±3.9 μM for genistein or 67.4±12.2 μM for daidzein. Combination treatments with genistein or daidzein produced EC50 of 57.6±2.0 or 29.7±2.4 μM for methotrexate, respectively. The combination index (CI) was 1.9 for methotrexate-genistein whilst CI was 1.1 for methotrexate-daidzein near the median dose. Values for CI decreased from 5.0 towards 1.0 as the ratio of methotrexate: isoflavone increased. The results are discussed in terms of prevailing ideas concerning how phytochemicals affects drug adsorption, distribution, metabolism and excretion (ADME) and the expected consequences for cytotoxicity.Conclusions: Treatment of MDA-MB-231 breast cancer cells with methotrexate and genistein or daidzein produces interactions consistent with antagonism (CI =1.1-5.0) but the effects are predicted to diminish with rising methotrexate to isoflavone ratio.
Highlights
Methotrexate is used frequently for treating leukemia, solid tumors and rheumatoid arthritis [1]
Methotrexate, genistein, daidzein, 3-(4,5dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), dimethyl Sulfoxide (DMSO) and other chemicals were obtained from SigmaAldrich (UK).Human breast cancer cell line MDAMB-231 was from American Type Cell Culture Collection (LGC Standards Teddington, Middlesex, UK)
A diverse range of potential interactions may occur between genistein and methotrexate that go to produce antagonism with regard to cytoxicity for MDA-MB-231 cells
Summary
Methotrexate is used frequently for treating leukemia, solid tumors and rheumatoid arthritis [1]. Acquired resistance to methotrexate [2] prompts high-dose therapy leading to a likelihood of toxic side-effects [3]. Combination therapy with antioxidant phytochemicals was proposed to mitigate the toxic side effects associated with methotrexate but the impact on drug effectiveness remains controversial [4,5,6]. Observational studies showed there were low rates of breast cancer incidence in Asian women linked to the consumption of soy products [7]. A variety of soybean products were found to prevent methotrexate gastro-intestinal toxicity, but the anti-apoptotic components appeared to be relatively high molecular weight (>10 kd) compounds [8]. Soy isoflavones possess anticancer activity [9,10]. Genistein produces synergisms with other anticancer agents due to a chemo-sensitizing effect [10,11]
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