In liver, the prodrug proguanil metabolizes into active metabolite cycloguanil, which inhibit folic acid synthesis in plasmodium by inhibiting dihydrofolate reductase (DHFR) enzyme. Proguanil is mostly used in combination with atovaquone as anti-malarial therapy. Regarding repurposing of proguanil as anti-cancer drug, not much has been explored yet, except one recent study, where they showed that proguanil suppress breast cancer cell proliferation by generating ROS and disruption of mitochondrial membrane potential. OGG1 is a base excision repair (BER) enzyme involved in recognition and excision of lethal oxidized guanine (8-oxoG) from DNA, which forms due to oxidative stress in cancer cells. Presence of such toxic lesions in DNA leads to replication stress and cell death. In our recent study, we found that suppression of OGG1, either by shRNA or by using specific OGG1 inhibitor TH5487, significantly reduces proliferation of many different cancer cell types. This effect is due to a decrease in mitochondrial membrane potential and increased replication stress. In the present study, we have been exploring if OGG1 depleted cells became more sensitive to proguanil based on its property to induce ROS mediated oxidative stress in the cancer cells. OGG1 depleted AML cancer cell line A3 was more sensitive to proguanil treatment in comparison to non-target control. Furthermore, we also found synergistic drug-drug interaction between TH5487 and proguanil in AML cell lines, A3, HL60, THP1, colon cancer cell line HCT116, lung cancer cell line H460, bladder cancer NTUB1, osteosarcoma cell line U2OS, while less pronounced effect was observed in lymphoblastoid cell lines, suggesting cancer specificity of drug combination. Combination treatment of TH5487 with proguanil induced more ROS and DNA damage in cancer cells in comparison to DMSO control, TH5487 or proguanil alone. No target engagement or stabilization was observed with DHFR in human osteosarcoma cells, even after 24hrs of treatment with proguanil using by CESTA method. This implies DHFR independent inhibition of unknown target, which enhance the toxicity of OGG1 inhibitor in cancer cell or vice versa. In conclusion, our preliminary investigation suggests that proguanil in combination with OGG1 inhibitor synergistically kill cancer cells and in-depth studies are required to validate the unknow target of proguanil in cancer cells to use proguanil as anti-cancer drug either alone or in combination.

Citation Format: Varshni Rajagopal, Karthick Marimuthu, Carlos Benitez-Buelga, Olov Wallner, Evert Homan, Martin Scobie, Christina Kalderén, Thomas Helleday, Ulrika Warpman Berglund, Kumar Sanjiv. OGG1 depleted cancer cells are sensitive to anti-malarial drug proguanil: Repurposing for cancer treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4799.

©2020 American Association for Cancer Research.
2020
American Association for Cancer Research.