Abstract

Background: Chia seed is an oil seed with multiple biological activities. Doxorubicin is 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, which may lead to increased apoptosis.

Conclusion: 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.

Keywords: Chia seed oil, resistance to liposomal-doxorubicin, HCC, tumor-suppressing miRNAs, CYP-3A4, MRP1.