Mitochondrial Complex I Inhibitors Expose a Vulnerability for Selective Killing of Pten-Null Cells.
Cell Rep
; 23(1): 58-67, 2018 04 03.
Article
em En
| MEDLINE
| ID: mdl-29617673
ABSTRACT
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.
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MEDLINE
Assunto principal:
Neoplasias da Próstata
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Rotenona
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Complexo I de Transporte de Elétrons
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Inibidores Enzimáticos
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Fibroblastos
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Antineoplásicos
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article