Increasingly cancer is being viewed as a channelopathy because the passage of ions via ion channels and transporters mediate the regulation of tumor cell survival, death, and motility. As a result, a potential targeted therapy for cancer is to use venom peptides that are selective for ion channels and transporters overexpressed in tumor cells. Here we describe the selectivity and mechanism of action of terebrid snail venom peptide, Tv1, for treating the most common type of liver cancer, hepatocellular carcinoma (HCC). Tv1 inhibited the proliferation of murine HCC cells and significantly reduced tumor size in Tv1-treated syngeneic tumor-bearing mice. Tv1’s mechanism of action involves binding to overexpressed transient receptor potential (TRP) channels leading to calcium dependent apoptosis resulting from down-regulation of cyclooxygenase-2 (COX-2). Our findings demonstrate the importance of modulating ion channels and the unique potential of venom peptides as tumor specific ligands in the quest for targeted cancer therapies.

A strategy for treating the most common type of liver cancer, hepatocellular carcinoma (HCC) applies a targeted therapy using venom peptides that are selective for ion channels and transporters overexpressed in tumor cells. Here, we report selective anti-HCC properties of Tv1, a venom peptide from the predatory marine terebrid snail, Terebra variegata. Tv1 was applied in vitro to liver cancer cells and administered in vivo to allograft tumor mouse models. Tv1 inhibited the proliferation of murine HCC cells via calcium dependent apoptosis resulting from down-regulation of the cyclooxygenase-2 (COX-2) pathway. Additionally, tumor sizes were significantly reduced in Tv1-treated syngeneic tumor-bearing mice. Tv1’s mechanism of action involves binding to specific transient receptor potential (TRP) cation channels that are overexpressed in HCC cell models. Our findings demonstrate the unique potential of venom peptides to function as tumor specific ligands in the quest for targeted cancer therapies.