Chia Seeds Oil Suppresses the Resistance of Hepatocellular Carcinoma Cells to Liposomal-doxorubicin and Upregulates the Tumor Suppressor miRNAs.

Abstract

Chia seed is an oil seed with multiple biological activities. Doxorubicin is effective chemotherapy for liver cancer. Resistance and adverse effects are doxorubicin limitations. This study aimed to investigate the effect of chia seeds oil (CSO) on the resistance of HepG2 cells to liposomal-doxorubicin (DOX). The objective were investigated through measuring cytotoxicity, doxorubicin-metabolizing enzyme Cytochrome P450 3A4 (CYP-3A4), multidrug resistance-associated protein (MRP1), and the expression of multiple tumor suppressor microRNAs. The findings indicated that low concentration of CSO increased HepG2 cells' sensitivity to DOX, as concluded from its higher cytotoxicity. DOX-induced mRNAs of CYP-3A4 and MRP1 and their protein levels. CSO inhibited both in DOX-treated cells. CSO-induced tumor suppressor miRNAs. Doxorubicin inhibited miR-122 and let-7/b/e expression, while it led to overexpression of let- 7a. CSO/DOX upregulated let-7/b/e, miR-34a, and miR-122 (which inhibits MRP1) and downregulated let-7a, which may lead to increased apoptosis. CSO effectively re-sensitized HepG2 cells to liposomal-doxorubicin via inhibiting MRP1 and CYP-3A4, which may increase in vivo doxorubicin bioavailability and decrease its therapeutic dose to diminish its adverse effects.