| First Author | Naguib A | Year | 2018 |
| Journal | Cell Rep | Volume | 23 |
| Issue | 1 | Pages | 58-67 |
| PubMed ID | 29617673 | Mgi Jnum | J:271152 |
| Mgi Id | MGI:6279156 | Doi | 10.1016/j.celrep.2018.03.032 |
| Citation | Naguib A, et al. (2018) Mitochondrial Complex I Inhibitors Expose a Vulnerability for Selective Killing of Pten-Null Cells. Cell Rep 23(1):58-67 |
| abstractText | 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. |
