Sorafenib (SOR) is the only approved molecular targeted agent for the treatment of hepatocellular carcinoma (HCC), however, its use is delayed by the recently articulated safety concerns.
The present study aimed to test the hypothesis that combining snake venoms (SVs) or its ingredient l-amino acid oxidase (LAAO) could synergistically enhance the anti-proliferative effects of SOR at low doses on liver cancer cells (HepG2) versus normal liver cells (THLE2).
The cytotoxic effects were measured on HepG2 and THLE-2 using MTT assay. Gene expression for apoptotic, inflammatory, antioxidant and cell cycle regulator genes was detected by real-time PCR. The number of cells in each cell cycle phase was determined by flow cytometry.
SV, LAAO, and SOR exhibited higher cytotoxicity on HepG2 cells than THLE2 cells with the 2 combinations (2 LAAO + 3/4 SOR and 3 LAAO + 3/4 SOR) showed a potent synergistic anti-tumor effect on HepG2 while being safer on THLE-2. These 2 combinations significantly elevated the expression of apoptotic (Bax, caspase 3, 8, 9, p21), inflammatory (IL6, IL1β), and antioxidant (Nrf2 and HO-1) genes, and significantly decreased the expression of the anti-apoptotic Bcl2 and DNA topoisomerase 2-binding protein 1 (Topbp1) genes relative to the single treatment. Besides, there were a significant increase in MDA and SOD but a significant decrease in GPx and CAT activity in combined and single treatments with SOR versus the untreated control. The combined therapy also arrested HepG2 in the G2/M phase.
Our results suggest a novel synergistic, selective, inflammatory, and anti-proliferative effect of SV or LAAO with SOR on HepG2 cells. These 2 novel combinations could serve as a potential tool for the development of a novel therapeutic approach against HCC.