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

Abstract

Background: Chia seed is an oil-seed of multiple biological activities. Doxorubicin is an effective chemotherapy for liver cancer. Resistance and adverse effects are doxorubicin limitations. Objective: This study aimed to investigate the effect of chia seeds oil (CSO) on the resistance of HepG2 cells to liposomal-doxorubicin (DOX). Methods: 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. Results: 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 that may lead to increased apoptosis. Conclusion: CSO effectively re-sensitized HepG2 cells to liposomal-doxorubicin via inhibiting MRP1 and CYP-3A4 that may increase in vivo doxorubicin bioavailability and decrease its therapeutic dose to diminish its adverse effects.