Melatonin enhances the anti-tumor effect of sorafenib via AKT/p27-mediated cell cycle arrest in hepatocarcinoma cell lines

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, often diagnosed in late stages when most therapeutic methods are not very effective. The introduction of the multikinase inhibitor sorafenib as the standard of care has opened a window of hope for patients with advanced HCC, patients with very poor prognosis; however, patients usually develop acquired resistance to sorafenib limiting its therapeutic benefits. Melatonin (MT), an indoleamine compound produced in the pineal gland, has shown a substantial beneficial effect in increasing the efficacy of common anticancer drugs and decreasing their toxic effects. Here we demonstrate that MT potentiated the sorafenib-mediated inhibition of cell viability and colony formation in HCC cell lines. Moreover, combined treatment of MT and sorafenib enhanced the cell cycle arrest of HCC cells at the G0/G1 phase. Co-treatment of sorafenib and MT was found to upregulate p27, an inhibitor of several cyclin-dependent kinases (CDK), and downregulate p-AKT, c-myc, cyclin D1 and CDK4/6 protein expression. Furthermore, overexpression of p-AKT using SC79 reversed the effect of sorafenib and MT combination on cell viability and growth of HCC cells. These results suggest that the AKT pathway might be critical for the enhanced anticancer effect observed after co-treatment with MT and sorafenib. Taken together, our findings demonstrated that AKT/p27-mediated cell growth arrest induced by MT increased the sensitivity of HCC cells to the effect of sorafenib.

Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review

“…Indeed, the combination of 0.2–2 mM melatonin and sorafenib enhanced the cell cycle arrest at G0/G1 phase in both Bel-7402 and SMMC-7721 HCC cell lines by upregulating p27—an inhibitor of several CDKs, and downregulating p -AKT and also different proteins including c-myc, cyclin D1 and CDK4/6, which play key roles in cell proliferation. These results were validated using an in vivo model of xenograft tumor treated with 25 mg/kg body weight (daily for 18 days) [ 46 ]. More recently, a preliminary study using HepG2 HCC cells, has also confirmed that 3 mM melatonin increased the antiproliferative effects of (–)-epigallocatechin-3-gallate (EGCG) through a p21-associated mechanism [ 56 ].…”

Predicting therapeutic drugs for hepatocellular carcinoma based on tissue-specific pathways

“…Ajmaline can alter the intracellular K+ ion concentration by blocking the cell Na+/K+ channels, and it has been proved to be cytotoxic to tumor cells in our experiments, which proves that ajmaline has potential therapeutic value, although it has similar cytotoxicity to normal liver cells [ 85 ]. In fact, in a culture environment, some excellent targeted therapeutic drugs, such as sorafenib, will also have similar cytotoxicity to normal cell lines [ 86 ]. This may be due to the drugs inhibiting the corresponding regulatory pathways and leading to undifferentiated cell death, regardless of whether the cell line is a normal cell line or a cancer cell line.…”

Multiple interactions between melatonin and non‐coding RNAs in cancer biology

“…In the study of Long at el, MT along with sorafenib inhibits the cell cycle of hepatocellular carcinoma (HCC) cells in the G0/G1 phase. It can also be prevented by upregulate P27, which inhibits several cyclin‐dependent kinases (CDK) and down‐regulates p‐AKT, c‐myc, cyclin D1, and CDK4/6 protein expression preventing the transfer of the cell cycle from stage G1 to S (Long et al., 2017). Cos et al observed that MT has a direct inhibitory effect on the proliferation of MCF‐7 human breast cancer cells by increasing the duration of the cell cycle.…”