Triazole derivatives of guttiferone-A inhibit the proliferation of HepG2 cells by modulating MAPK/ERK signaling and expression profiles of regulators of G1/S transition

Abstract

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. The mortality rate has not reduced despite introducing new therapeutic approaches such as immunotherapy and target-directed therapies. Drug resistance represents a challenge for HCC treatment, resulting in the search for new drug candidates. In the present study, a series of triazole derivatives of guttiferone-A were synthesized and tested against non-small-cell lung cancer (A549), hepatocellular carcinoma (HepG2), and estrogen-positive breast carcinoma (MCF-7) cell lines. Compounds 6, 10, and 12 displayed significant cytotoxic activity on A549 and HepG2 cells, and compound 10 was highly selective toward HepG2 cells. Compound 10 inhibited MAPK/ERK signaling and modulated the expression of critical regulators of the cell cycle progression in HepG2 cells. There was a significant reduction of the cyclins D/E, while p21 was upregulated, indicating that the antiproliferative activity of compound 10 on HepG2 cells, at least in part, is associated with its ability to modulate the expression profile of regulators of G1/S transition. Our findings showed that triazole derivatives of guttiferone-A may be useful as anticancer prototypes and support further in vivo investigation to evaluate the efficiency of compound 10 in suppressing HCC growth and progression.