ABT-737 and pictilisib synergistically enhance pitavastatin-induced apoptosis in ovarian cancer cells
ABT-737 and pictilisib synergistically enhance pitavastatin-induced apoptosis in ovarian cancer cells
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DOI：
10.3892/ol.2017.7516
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发表时间：
2018-02-01
期刊：
影响因子：
2.9
通讯作者：
Richardson, Alan
中科院分区：
文献类型：
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作者：
De Wolf, Elizabeth;De Wolf, Christopher;Richardson, Alan
人们对重新部署药物与其他肿瘤治疗方法联合使用有着很大的兴趣。他汀类药物在卵巢癌中的单药活性已被广泛报道，但导致细胞死亡所需的药物浓度远高于接受他汀类药物治疗高胆固醇血症的患者所达到的浓度。不幸的是，高剂量服用他汀类药物会导致肌病。解决此问题的一种方法是确定可与他汀类药物联合使用以减少所需剂量的药物以及可能降低不良副作用发生率的药物。当 BH3 模拟物 ABT-737 或磷脂酰肌醇 3-激酶抑制剂 pictilisib 与匹伐他汀联合使用 Ovcar-3 和 Igrov-1 细胞进行细胞生长测定时，药物组合比单独使用匹伐他汀更有效。为了支持这一点，ABT-737 或 pictilisib 显着增加了匹伐他汀在几种卵巢癌细胞系中诱导的细胞死亡。这些药物在细胞凋亡测定中也具有协同作用。这些观察结果表明，BH3 模拟物或 pictilisib 与匹伐他汀联合可用于卵巢癌的一部分，特别是对 BH3 模拟物以及磷酸酶和张力蛋白同源物抑制敏感的卵巢肿瘤。
There is considerable interest in redeploying drugs for use in combination with other oncology therapeutics. The single-agent activity of statins in ovarian cancer has been widely reported, however the drug concentration required to cause cell death is considerably higher than that achieved in patients receiving statin treatment for hypercholesterolemia. Unfortunately, statins can cause myopathy when administered in high doses. One solution to this is to identify drugs that could be used in combination with statins to reduce the dose required and those that may potentially reduce the incidence of adverse side effects. When the BH3 mimetic ABT-737, or the phosphatidylinositol 3-kinase inhibitor pictilisib, were combined with pitavastatin in cell growth assays using Ovcar-3 and Igrov-1 cells, the drug combinations were more effective than pitavastatin alone. In support of this, ABT-737 or pictilisib markedly increased cell death induced by pitavastatin in several ovarian cancer cell lines. The drugs were also synergistic in apoptosis assays. These observations suggested that either BH3 mimetics or pictilisib in combination with pitavastatin could be used in a subset of ovarian tumours, particularly those sensitive to BH3 mimetics, and phosphatase and tensin homolog inhibition, in the treatment of ovarian cancer.