Journal of Chemical and Pharmaceutical Research (ISSN : 0975-7384)

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Synergistic inhibition of drug resistant breast cancer cells growth by the combination of luteolin and tamoxifen involves Nrf2 downregulation

Author(s): Mohammad Ali Esmaeili

Elevated expression of NF-E2-related factor 2 (Nrf2), a nuclear transcription factor, is a frequent genetic abnormality and is an important contributor to chemoresistance in cancer therapy. To further characterize its biological significance, the response of Nrf2 on the synergistic cytotoxic effect of luteolin and tamoxifen was investigated in tamoxifen resistant breast cancer (MCF-7/TAM) cells. Tamoxifen-resistant human breast cancer cells (MCF7/TAM) were treated with tamoxifen and luteolin alone and in combination at different concentration for 24 h. The cell viability was detected by 3-(4,5-dimethiylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. The transfection of siRNA was performed using Lipofectamine 2000 Reagent and the expression levels of Nuclear factor erythroid-2 p45-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were detected by Western blotting. Our results showed that combination treatment significantly sensitizes MCF-7/TAM cells to tamoxifen, which was accompanied by suppression of Nrf2 activation and decreased expression of HO-1. While overexpression of Nrf2 in tamoxifen resistant breast cancer cells conferred protection against the cytotoxicity caused by their combination, knockdown of Nrf2 expression using siRNA techniques enhanced their cytotoxic effect. These results suggested that luteolin in combination with tamoxifen can reversed tamoxifen resistance in MCF-7/TAM cells in synergic manner, at least in part, through suppression of Nrf2 signaling.

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