Abstract 1378: Proguanil inhibits breast cancer in vitro and in vivo through mitochondrial dysfunction

Abstract Breast cancer remains the second leading cause of cancer-related death among women in the U.S. New treatments for this aggressive disease are thus urgently needed. Repurposing FDA-approved non-cancer drugs for cancer treatment is an alternative that saves time and lowers the costs needed for drug development. In this study, we investigated the effects of proguanil, an anti-malarial drug, in breast cancer cells. Proguanil exhibited a significant cytotoxic effect on various breast cancer cell lines including patient derived cell lines through induction of apoptosis. Our results indicated that proguanil treatment caused a 3-fold increased production of ROS compared with control and reduced the mitochondrial membrane potential, mitochondrial respiration rate, and ATP production. Our studies also revealed the phosphorylation of H2AX, a marker for DNA damage. Proguanil treatment further increased the expression of apoptotic markers Bax, cleaved PARP, cleaved-caspase 9, and down-regulated anti-apoptotic Bcl-2 and survivin in breast cancer cells. Oral administration of 20mg/kg of proguanil significantly inhibited the tumor growth by 55% in mice model. Western blot analyses of tumors from proguanil-treated group showed increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 compared to control. Taken together, our results demonstrate the anti-cancer effect of proguanil by targeting mitochondria, and can be considered for clinical investigation against breast cancer. Citation Format: Marina Curcic, Nehal Gupta, Sanjay K. Srivastava. Proguanil inhibits breast cancer in vitro and in vivo through mitochondrial dysfunction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1378.