Respiratory Capacity and Reserve Predict Cell Sensitivity to Mitochondria Inhibitors: Mechanism-Based Markers to Identify Metformin-Responsive Cancers

Abstract Metformin has been extensively studied for its impact on cancer cell metabolism and anticancer potential. Despite evidence of significant reduction in cancer occurrence in diabetic patients taking metformin, phase II cancer trials of the agent have been disappointing, quite possibly because of the lack of molecular mechanism-based patient stratification. In an effort to identify cancers that are responsive to metformin, we discovered that mitochondria respiratory capacity and respiratory reserve, which vary widely among cancer cells, correlate strongly to metformin sensitivity in both the in vitro and in vivo settings. A causal relationship between respiratory function and metformin sensitivity is demonstrated in studies in which we lowered respiratory capacity by either genetic knockdown or pharmacologic suppression of electron transport chain components, rendering cancer cells more vulnerable to metformin. These findings led us to predict, and experimentally validate, that metformin and AMP kinase inhibition synergistically suppress cancer cell proliferation.