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National Institute of Environmental Health Sciences

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Publication Detail

Title: Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.

Authors: Guo, Zhijun; Sevrioukova, Irina F; Denisov, Ilia G; Zhang, Xia; Chiu, Ting-Lan; Thomas, Dafydd G; Hanse, Eric A; Cuellar, Rebecca A D; Grinkova, Yelena V; Langenfeld, Vanessa Wankhede; Swedien, Daniel S; Stamschror, Justin D; Alvarez, Juan; Luna, Fernando; Galván, Adela; Bae, Young Kyung; Wulfkuhle, Julia D; Gallagher, Rosa I; Petricoin Rd, Emanuel F; Norris, Beverly; Flory, Craig M; Schumacher, Robert J; O'Sullivan, M Gerard; Cao, Qing; Chu, Haitao; Lipscomb, John D; Atkins, William M; Gupta, Kalpna; Kelekar, Ameeta; Blair, Ian A; Capdevila, Jorge H; Falck, John R; Sligar, Stephen G; Poulos, Thomas L; Georg, Gunda I; Ambrose, Elizabeth; Potter, David A

Published In Cell Chem Biol, (2017 Oct 19)

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.

PubMed ID: 28919040 Exiting the NIEHS site

MeSH Terms: AMP-Activated Protein Kinases/metabolism; Animals; Biguanides/chemistry; Biguanides/metabolism*; Biguanides/pharmacology*; Breast Neoplasms/pathology; Catalytic Domain; Cell Respiration/drug effects; Cytochrome P-450 CYP3A/chemistry; Cytochrome P-450 CYP3A/deficiency; Cytochrome P-450 CYP3A/genetics; Cytochrome P-450 CYP3A/metabolism*; Estrogen Receptor alpha/genetics; Female; Gene Expression Regulation, Neoplastic/drug effects; Gene Silencing; Heme/metabolism*; Humans; MCF-7 Cells; Membrane Potential, Mitochondrial/drug effects; Mice; Mitochondria/drug effects*; Mitochondria/metabolism; Mitochondria/pathology; Models, Molecular; Protein Transport/drug effects

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