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

Abstract

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.

Mitochondrial complex I inhibitor deguelin induces metabolic reprogramming and sensitizes vemurafenib‐resistant BRAFV600E mutation bearing metastatic melanoma cells

“…Interestingly, our results are consistent with another recent screen that identified deguelin and rotenone as compounds effective against PTEN-null cells in the context of prostate cancer, 30 potentially suggesting additional reasons for the results we have observed.…”

“…For that reason, the results of our high‐throughput screening made sense as we identified the electron transport chain inhibitors rotenone and deguelin as two of the three most potent compounds against vemurafenib‐treated BRAF V600E /PTEN‐null A2058 melanoma cells. Interestingly, our results are consistent with another recent screen that identified deguelin and rotenone as compounds effective against PTEN‐null cells in the context of prostate cancer, potentially suggesting additional reasons for the results we have observed.…”

GDA, a web-based tool for Genomics and Drugs integrated analysis

“…We took advantage of a loss-of-function PTEN signature (PTEN_DN.V1_UP gene set of the Molecular Signatures Database; http://software.broadinstitute.org/gsea/msigdb/index.jsp ) obtained from isogenic tumor cell line pairs in which PTEN was inactivated through RNA interference ( 24 ) to identify drugs with selective cytotoxicity for cancer cells showing PTEN inactivation. To this aim, we used the from signature to drug analysis and, among the compounds predicted to be active on all tissues, we found several mitochondrial inhibitors (as Leucinostatin-A, Ossamycin, Cytovaricin, Oligomycin-A, Oligomycin-B, and Oligomycin-C; Figure 4A ) that have been recently demonstrated to be selective cytotoxic drugs for PTEN-null cancer cells ( 25 ). Conversely, we used the from drug to signature module to identify signaling pathways active in cells responsive to mitochondrial inhibitors.…”

Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment

“…This latter class of compounds has aroused particular interest in recent years, proving to be a promising scaffold for anticancer candidates, active at sub-nanomolar concentrations. Regardless of their chemical class, complex I inhibitors, alone or in association with molecules shifting tumor metabolism towards oxidative phosphorylation, have shown a high antitumor potential against different types of cancer cells studied both in in vitro and in vivo models [ 33 , 34 , 35 , 36 ].…”