Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, Liaoning Province 110016, PR China.
Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning Province 110016, PR China; State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, Guangdong Province 518055, PR China.
Biochem Pharmacol. 2022 Jul;201:115093. doi: 10.1016/j.bcp.2022.115093. Epub 2022 May 14.
Hepatocellular carcinoma (HCC) is one of the most malignant tumors worldwide with high lethality and prevalence. The deregulated phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway plays an indispensable role in mediating the progression of HCC. Among them, PI3K acts as the most pivotal initiator, contributing to multiple malignant biological processes, like proliferation, apoptosis and angiogenesis. Many PI3K inhibitors (PI3Kis) have been proved or proceeded into clinical as antineoplastic drugs. Nevertheless, the application of PI3Kis for the treatment of HCC remains a blank. Accordingly, our study identified a novel PI3Ki (DZW-310) with strong anti-HCC activity in vitro and in vivo. This study aimed to evaluate its anti-HCC effect and elucidate its potential mechanism. Our current results revealed that DZW-310 significantly attenuated HCC cell growth through promoting intrinsic apoptosis and G0/G1 phase cell arrest. Moreover, DZW-310 suppressed angiogenesis by regulating the HIF-1α/VEGFA axis. Further mechanistic investigation demonstrated that DZW-310, functioned as a PI3Ki, exerted strong anti-HCC activity by acting on PI3Kα (a major subtype of PI3K) and ulteriorly deactivating the PI3K/AKT/mTOR pathway. Collectively, our studies identified that DZW-310 is expected to become a promising HCC therapeutic agent and broaden clinical application of PI3Ki in HCC chemotherapy.
肝细胞癌（HCC）是全球最恶性的肿瘤之一，具有高致死率和高患病率。失调的磷脂酰肌醇 3-激酶/蛋白激酶 B/雷帕霉素靶蛋白（PI3K/AKT/mTOR）通路在介导 HCC 的进展中起着不可或缺的作用。其中，PI3K 作为最关键的启动子，参与多种恶性生物学过程，如增殖、凋亡和血管生成。许多 PI3K 抑制剂（PI3Ki）已被证明或已进入临床作为抗肿瘤药物。然而，PI3Ki 在 HCC 治疗中的应用仍然是空白。因此，我们的研究在体外和体内鉴定了一种新型的 PI3Ki（DZW-310），具有很强的抗 HCC 活性。本研究旨在评估其抗 HCC 作用并阐明其潜在机制。我们目前的结果表明，DZW-310 通过促进内在凋亡和 G0/G1 期细胞阻滞显著抑制 HCC 细胞生长。此外，DZW-310 通过调节 HIF-1α/VEGFA 轴抑制血管生成。进一步的机制研究表明，DZW-310 作为 PI3Ki，通过作用于 PI3Kα（PI3K 的主要亚型）并进一步使 PI3K/AKT/mTOR 通路失活，发挥强大的抗 HCC 活性。总之，我们的研究表明，DZW-310 有望成为一种有前途的 HCC 治疗药物，并拓宽 PI3Ki 在 HCC 化疗中的临床应用。
