Proguanil Suppresses Breast Tumor Growth In Vitro and In Vivo by Inducing Apoptosis via Mitochondrial Dysfunction.

Simple Summary: This study is focused on exploring the anticancer properties of proguanil, an old antimalarial drug. Proguanil demonstrated a significant ability to induce cell death through the increased production of reactive oxygen species (ROS) and subsequent disruption in mitochondrial function in breast cancer cells. In several breast cancer cell lines and mouse tumor models, proguanil showed promising results by inhibiting tumor growth and altering key proteins associated with cancer progression. These findings suggest that proguanil could be a promising candidate for further clinical investigation as a potential treatment option for breast cancer. Breast cancer, ranking as the second leading cause of female cancer-related deaths in the U.S., demands the exploration of innovative treatments. Repurposing FDA-approved drugs emerges as an expedited and cost-effective strategy. Our study centered on proguanil, an antimalarial drug, reveals notable anti-proliferative effects on diverse breast cancer cell lines, including those derived from patients. Proguanil-induced apoptosis was associated with a substantial increase in reactive oxygen species (ROS) production, leading to reduced mitochondrial membrane potential, respiration, and ATP production. Proguanil treatment upregulated apoptotic markers (Bax, p-H2AX, cleaved-caspase 3, 9, cleaved PARP) and downregulated anti-apoptotic proteins (bcl-2, survivin) in breast cancer cell lines. In female Balb/c mice implanted with 4T1 breast tumors, daily oral administration of 20 mg/kg proguanil suppressed tumor enlargement by 55%. Western blot analyses of proguanil-treated tumors supported the in vitro findings, demonstrating increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 as compared to controls. Our results collectively highlight proguanil's anticancer efficacy in vitro and in vivo in breast cancer, prompting further consideration for clinical investigations. [ABSTRACT FROM AUTHOR]