Acyl-CoA synthetase 4 (ACSL4) is part of the acquisition of anticancer drug resistant in cancer

ORLANDO UO; MALOBERTI PM; SOLANO AR; CASTILLO AF; PODESTA EJ

Cordoba

Congreso; 52 th Annual Meeting Argentine Society for Biochemistry and Molecular Biology; 2016

52 th Annual Meeting Argentine Society for Biochemistry and Molecular Biology

The most common reason for acquisition of resistance to anticancer drugs is expression of multidrug resistant proteins (MRP) that detect and eject anticancer drugs from cells. For triple-negative breast cancer treatment, there is renewed interest in investigating the role of chemotherapy, however still there is a significant toxic effect of these drugs.Here we demonstrate that sensitivity of different breast cancer cell lines to chemotherapy agents correlates inversely with ACSL4 expression. Using the MCF-7 Tet-Off/ACSL4 model, we show a significant inhibition of cell proliferation at 20 uM of both carboplatin and cisplatin in ACSL4 expressing cells vs. an inhibition at 5 uM and 2.5 uM of carboplatin and cisplatin respectively in control cells.By ACSL4 expression up or down regulation, we demonstrate a regulation of several MRP genes. Combination of the inhibition of ACSL4 activity with cisplatin or carboplatin produces a significant synergistic effect to reduce tumor growth in the triple negative human breast cancer cell line. Strikingly the doses used of both agents did not produce any effect per se, suggesting the probability of reducing the toxic side effects of these agents when used in effective doses. Such a synergistic effect may not only be due to the inactivation of MRP genes but also to the inhibition of parallel pathways supporting tumor survival.