Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, China.
Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Zhongda Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, China.
Chem Biol Interact. 2023 Feb 1;371:110343. doi: 10.1016/j.cbi.2023.110343. Epub 2023 Jan 6.
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.
肝细胞癌 (HCC) 是全球最常见的恶性肿瘤之一，其临床治疗仍然具有挑战性。开发新的治疗方案对于有效的 HCC 治疗非常重要。磷脂酰肌醇 3-激酶 (PI3K) 是一种脂质激酶，在细胞生长和代谢中发挥重要作用，近 50%的 HCC 患者过度表达。研究表明，PI-3065 是一种磷酸肌醇 3-激酶 δ 的小分子抑制剂，可显著抑制实体乳腺癌。然而，其对 HCC 的抗肿瘤作用及其潜在机制尚不清楚。在本研究中，我们发现 PI-3065 呈剂量和时间依赖性地降低 HCC 细胞活力并诱导细胞凋亡，而对正常肝细胞没有明显的凋亡毒性。进一步的机制分析表明，PI-3065 主要通过抑制生存素蛋白表达、降低线粒体膜电位和促进细胞色素 C 释放来诱导细胞凋亡。同时，PI-3065 显著抑制 HCC 细胞的集落形成、迁移和上皮间质转化能力。此外，移植 HCC 肿瘤的裸鼠表明，PI-3065 通过靶向生存素在体内抑制 HCC 肿瘤生长。总之，PI-3065 特异性抑制生存素表达并在体内和体外发挥抗 HCC 活性，表明它可能成为 HCC 治疗的有效抗肿瘤药物，值得进一步研究。
