Mitochondrial Complex I Inhibitors Expose a Vulnerability for Selective Killing of Pten-Null Cells

Summary A hallmark of advanced prostate cancer (PC) is the concomitant loss of PTEN and p53 function. To selectively eliminate such cells, we screened cytotoxic compounds on Pten −/− ; Trp53 −/− fibroblasts and their Pten -WT reference. Highly selective killing of Pten -null cells can be achieved by deguelin, a natural insecticide. Deguelin eliminates Pten -deficient cells through inhibition of mitochondrial complex I (CI). Five hundred-fold higher drug doses are needed to obtain the same killing of Pten -WT cells, even though deguelin blocks their electron transport chain equally well. Selectivity arises because mitochondria of Pten -null cells consume ATP through complex V, instead of producing it. The resulting glucose dependency can be exploited to selectively kill Pten -null cells with clinically relevant CI inhibitors, especially if they are lipophilic. In vivo , deguelin suppressed disease in our genetically engineered mouse model for metastatic PC. Our data thus introduce a vulnerability for highly selective targeting of incurable PC with inhibitors of CI.