Institute for Science and Technology in Medicine, Guy Hilton Research Centre, Keele University, Thornburrow Drive, Stoke-on-Trent, ST4 7QB, UK.
Al-Salam Teaching Hospital, Nineveh Health Directorate, Ministry of Health, Mosul, Iraq.
Sci Rep. 2019 Jul 3;9(1):9632. doi: 10.1038/s41598-019-46102-1.
The survival rate for patients with ovarian cancer has changed little in the past three decades since the introduction of platinum-based chemotherapy and new drugs are needed. Statins are drugs used for the treatment and prevention of cardiovascular diseases. Recent work from our laboratory has shown that pitavastatin has potential as a treatment for ovarian cancer if dietary geranylgeraniol is controlled. However, relatively high doses of statins are required to induce apoptosis in cancer cells, increasing the risk of myopathy, the most common adverse effect associated with statins. This makes it desirable to identify drugs which reduce the dose of pitavastatin necessary to treat cancer. A drug-repositioning strategy was employed to identify suitable candidates. Screening a custom library of 100 off-patent drugs for synergistic activity with pitavastatin identified prednisolone as the most prominent hit. Prednisolone potentiated the activity of pitavastatin in several assays measuring the growth, survival or apoptosis in several ovarian cancer cells lines. Prednisolone, alone or in some cases in combination with pitavastatin, reduced the expression of genes encoding enzymes in the mevalonate pathway, providing a mechanistic explanation for the synergy.
过去三十年来，自从引入基于铂的化疗以来，卵巢癌患者的生存率变化不大，因此需要新的药物。他汀类药物是用于治疗和预防心血管疾病的药物。我们实验室最近的工作表明，如果控制饮食中的香叶基香叶醇，匹伐他汀有可能成为治疗卵巢癌的药物。然而，为了诱导癌细胞凋亡，需要使用相对较高剂量的他汀类药物，这增加了肌病的风险，肌病是与他汀类药物相关的最常见不良反应。因此，有必要寻找能够降低治疗癌症所需的匹伐他汀剂量的药物。采用药物重定位策略来识别合适的候选药物。筛选了一个由 100 种非专利药物组成的定制文库，以寻找与匹伐他汀协同作用的药物，结果发现泼尼松龙是最显著的候选药物。泼尼松龙在几种测量几种卵巢癌细胞系生长、存活或凋亡的实验中增强了匹伐他汀的活性。泼尼松龙单独使用或在某些情况下与匹伐他汀联合使用，降低了编码甲羟戊酸途径中酶的基因的表达，为协同作用提供了一种机制解释。
