PI3K δ inhibitor PI-3065 induces apoptosis in hepatocellular carcinoma cells by targeting survivin

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and its clinical treatment remains challenging. The development of new treatment regimens is important for effective HCC treatment. Phosphoinositide 3-kinase (PI3K) is a lipid kinase that plays an important role in cell growth and metabolism and is overexpressed in nearly 50% of patients with HCC. Studies have shown that PI-3065, a small-molecule inhibitor of phosphatidylinositol 3-kinase delta, significantly inhibits solid breast cancer. However, its antitumor effects against HCC and the underlying mechanisms remain unclear. In the present study, we found that PI-3065 dose- and time-dependently reduced HCC cell viability and induced apoptosis while posing no obvious apoptotic toxicity in normal liver cells. Further mechanistic analysis showed that PI-3065 induced apoptosis mainly by inhibiting survivin protein expression, decreasing mitochondrial membrane potential, and promoting cytochrome C release. Simultaneously, PI-3065 markedly suppressed the colony formation, migration, and epithelial–mesenchymal transition abilities of HCC cells. Furthermore, transplantation of nude mice with HCC tumors showed that PI-3065 inhibits HCC tumor growth in vivo by targeting survivin. In summary, PI-3065 specifically inhibited survivin expression and exerted anti-HCC activity in vivo and in vitro, suggesting that it may serve as an effective antitumor drug for HCC treatment, which warrants further study.