Int J Med Sci 2022; 19(2):233-241. doi:10.7150/ijms.67027 This issue

Research Paper

Proguanil synergistically sensitizes ovarian cancer cells to olaparib by increasing DNA damage and inducing apoptosis

Yan Wu1, Tianyu Wu1, Xin Hu2, Simeng Xu2, Di Xiao2, Jingtao Wu2, Xinjian Yan1, Xiaoping Yang2✉, Gaofeng Li1✉

1. Department of Oncology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou 412000, Hunan, China.
2. Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy School of Medicine, Hunan Normal University, Changsha 410013, Hunan, China.

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Citation:
Wu Y, Wu T, Hu X, Xu S, Xiao D, Wu J, Yan X, Yang X, Li G. Proguanil synergistically sensitizes ovarian cancer cells to olaparib by increasing DNA damage and inducing apoptosis. Int J Med Sci 2022; 19(2):233-241. doi:10.7150/ijms.67027. Available from https://www.medsci.org/v19p0233.htm

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Abstract

Graphic abstract

Ovarian cancer is the second leading cause of cancer-related deaths in women, with low five-year survival rates. Therefore, it is essential to seek new treatment options. Olaparib, a PARP inhibitor, has benefited many ovarian cancer patients, but olaparib is much less effective as a single agent in 50% of patients with high grade severe tumors. Proguanil, which was originally developed as an anti-malarial drug, has gained attention due to its anti-tumor effects. Here, we evaluated the anti-tumor effect of the combination of olaparib and proguanil on ovarian cancer cells, aimed to develop a potential medical option for treating ovarian cancer patients. We examined the effect on proliferation by MTT and colony formation assays, while cell migration was measured by the transwell assay. The effect on apoptosis was measured by flow cytometry and AO/EB staining assays. Western blotting was used to detect protein expression levels in cells treated with olaparib and/or proguanil. In addition, the synergistic effect of these two drugs is calculated by CompuSyn software. The combination of olaparib and proguanil significantly increased growth suppression and apoptosis in ovarian cancer cells, compared to either single agent alone. Furthermore, results showed that the combination of olaparib and proguanil synergistically increased olaparib-induced apoptosis and DNA damage and reduced the efficiency of DNA homologous recombination repair. Our findings indicate that combination of olaparib with proguanil will be a novel potential administration route for treating ovarian cancer patients.

Keywords: Proguanil, olaparib, ovarian cancer, combination therapy