Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.
Cell Chem Biol
; 24(10): 1259-1275.e6, 2017 Oct 19.
Article
em En
| MEDLINE
| ID: mdl-28919040
ABSTRACT
The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell-intrinsic EETs. Metformin bound to the active-site heme of CYP3A4 in a co-crystal structure, establishing CYP3A4 as a biguanide target. Structure-based design led to discovery of N1-hexyl-N5-benzyl-biguanide (HBB), which bound to the CYP3A4 heme with higher affinity than metformin. HBB potently and specifically inhibited CYP3A4 AA epoxygenase activity. HBB also inhibited growth of established ER+ mammary tumors and suppressed intratumoral mTOR. CYP3A4 AA epoxygenase inhibition by biguanides thus demonstrates convergence between eicosanoid activity in mitochondria and biguanide action in cancer, opening a new avenue for cancer drug discovery.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Biguanidas
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Citocromo P-450 CYP3A
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Heme
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Mitocôndrias
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article