Xiong, D.; Yin, Z.; Huang, M.; Wang, Y.; Hardy, M.; Kalyanaraman, B.; Wong, ST.; You, M.

Cancer Communications, 2023, 1-5

Atovaquone (ATO), a mitochondrial inhibitor, has anti-cancer effects. Based on ATO, we developed mitochondria-targeted atovaquone (Mito-ATO) that had even stronger anti-tumor efficacy than ATO. We synthesized Mito-ATO by attaching the bulky triphenylphosphonium (TPP) group to ATO via a ten-carbon alkyl chain. To assess the effects of Mito-ATO on tumor microenvironment, we conducted single-cell RNA sequencing (scRNA-seq) on treated immune cells from mice having lung tumors either treated with or without Mito-ATO.

In the present study, we found that Mito-ATO may differentially regulate pyruvate metabolism, glutamine metabolism and TCA cycle across immune cells with distinct roles in the TME.

The metabolic plasticity effects caused by Mito-ATO treatment may contribute to the overall efficacy of this drug on lung tumors. Mito-ATO’s parental compound –ATO has begun to be applied to anti-cancer clinical trials. Given that Mito-ATO is much more potent against human cancer cell lines compared to ATO, it is reasonable to predict that Mito-ATO has great potential in clinics.

Collaborations :

Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226 USA

Center for Cancer Prevention, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX, 77030 USA

Department of Systems Medicine and Bioengineering, Houston Methodist Cancer Center, Houston Methodist, Hospital, Weill Cornell Medicine, Houston, Texas, USA

Fundings :

International Research Program, SuperO₂ (CNRS), NIH, Grant ID: R01CA223804, R01CA232433, R01CA205633, and R01CA280746