Abstract
The resistance to sorafenib highly affects its clinical benefits for treating hepatocellular carcinoma (HCC). Sodium orthovanadate (SOV) is a phosphate analog that displays anti-cancer activities against various types of malignancies including HCC. The present study has demonstrated that SOV is able to overcome sorafenib resistance and strengthens sorafenib in suppressing sorafenib-resistant HCC cells in vitro and in animal models. Similar to its action on parental HCC cells, SOV induced cell cycle arrest at G2/M phases by regulating cyclin B1 and cyclin-dependent kinase 1, and apoptosis by reducing mitochondrial membrane potential, in sorafenib-resistant HCC cells. More importantly, SOV inhibited ATPase activity, which was significantly elevated in sorafenib-resistant HCC cells. SOV also reduced the expression of HIF-1α and HIF-2α and their nuclear translocation, resulting in downregulation of their downstream factors including vascular endothelial growth factor, lactate dehydrogenase-A and glucose transporter 1. Its ability to inhibit ATPase activity and hypoxia-inducible pathways enabled SOV to efficiently suppress both normoxic and hypoxic cells, which compose cancer cell populations inside sorafenib-resistant HCC tumors. The present results indicate that SOV may be a potent candidate drug for overcoming the resistance to sorafenib in treating HCC.
Highlights
Hepatocellular carcinoma (HCC) remains the third leading cause of cancer mortality worldwide[1]
The present results have revealed that Sodium orthovanadate (SOV) overcomes sorafenib resistance and strengthens sorafenib in suppressing SR-hepatocellular carcinoma (HCC) cells in vitro and in vivo
SOV inhibited ATPase activity, which was significantly elevated in sorafenib-resistant HCC (SR-HCC) cells
Summary
Hepatocellular carcinoma (HCC) remains the third leading cause of cancer mortality worldwide[1]. Inhibition of Na+/K+-ATPase re-sensitized multiple cancer cells to various chemotherapeutic drugs[8,11,12,13,14] It has not been investigated whether Na+/K+-ATPase is involved in the sorafenib resistance of HCC. Its molecular mechanisms remain unclear, SOV induces cell cycle arrest at G2/M phase and programmed cell death of cancer cells[21,22]. It is unknown whether it displays inhibitory activities against SR-HCC cells. It is well known that tumor hypoxia induces cancer drug resistance by activating hypoxic pathways, which are controlled by hypoxia-inducible factors (HIFs)[23,24]. It can be speculated that SOV as an ATPase inhibitor may inhibit HIF pathways in SR-HCC cells
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