Department of Pharmacology, School of Medicine, Zhejiang University City College.
Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University.
Anticancer Drugs. 2021 Aug 1;32(7):727-733. doi: 10.1097/CAD.0000000000001056.
Vinpocetine is widely used to treat cerebrovascular diseases. However, the effect of vinpocetine to treat hepatocellular carcinoma (HCC) has not been investigated. In this study, we revealed that vinpocetine was associated with antiproliferative activity in HCC cells, but induced cytoprotective autophagy, which restricted its antitumor activity. Autophagy inhibitors improved the antiproliferative activity of vinpocetine in HCC cells. Sorafenib is effective to treat advanced HCC, but the effect of autophagy induced by sorafenib is indistinct. We demonstrated vinpocetine plus sorafenib suppressed the cytoprotective autophagy activated by vinpocetine in HCC cells and significantly induced apoptosis and suppressed cell proliferation in HCC cells. In addition, vinpocetine plus sorafenib activates glycogen synthase kinase 3β (GSK-3β) and subsequently inhibits cytoprotective autophagy induced by vinpocetine in HCC cells. Meanwhile, overexpression of GSK-3β was efficient to increase the apoptosis induced by vinpocetine plus sorafenib in HCC cells. Our study revealed that vinpocetine plus sorafenib could suppress the cytoprotective autophagy induced by vinpocetine and subsequently show synergistically anti-HCC activity via activating GSK-3β and the combination of vinpocetine and sorafenib might reverse sorafenib resistance via the PI3K/protein kinase B/GSK-3β signaling axis. Thus, vinpocetine may be a potential candidate for sorafenib sensitization and HCC treatment, and our results may help to elucidate more effective therapeutic options for HCC patients with sorafenib resistance.
长春西汀广泛用于治疗脑血管疾病。然而，长春西汀治疗肝细胞癌（HCC）的效果尚未得到研究。在这项研究中，我们揭示了长春西汀与 HCC 细胞的增殖抑制活性有关，但诱导了细胞保护性自噬，限制了其抗肿瘤活性。自噬抑制剂提高了长春西汀在 HCC 细胞中的增殖抑制活性。索拉非尼是治疗晚期 HCC 的有效药物，但索拉非尼诱导的自噬作用并不明显。我们证明长春西汀联合索拉非尼抑制 HCC 细胞中长春西汀激活的细胞保护性自噬，并显著诱导 HCC 细胞凋亡和抑制细胞增殖。此外，长春西汀联合索拉非尼激活糖原合酶激酶 3β（GSK-3β），随后抑制 HCC 细胞中长春西汀诱导的细胞保护性自噬。同时，过表达 GSK-3β可有效增加 HCC 细胞中长春西汀联合索拉非尼诱导的凋亡。我们的研究表明，长春西汀联合索拉非尼可抑制长春西汀诱导的细胞保护性自噬，并通过激活 GSK-3β协同发挥抗 HCC 活性，长春西汀和索拉非尼的联合可能通过 PI3K/蛋白激酶 B/GSK-3β信号通路逆转索拉非尼耐药。因此，长春西汀可能是索拉非尼增敏和 HCC 治疗的潜在候选药物，我们的结果可能有助于为索拉非尼耐药的 HCC 患者阐明更有效的治疗选择。
