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Publication Abstract from PubMed

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 AMPKalpha. CYP3A4 knockdown activated AMPKalpha, 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.

Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.,Guo Z, Sevrioukova IF, Denisov IG, Zhang X, Chiu TL, Thomas DG, Hanse EA, Cuellar RAD, Grinkova YV, Langenfeld VW, Swedien DS, Stamschror JD, Alvarez J, Luna F, Galvan A, Bae YK, Wulfkuhle JD, Gallagher RI, Petricoin EF Rd, Norris B, Flory CM, Schumacher RJ, O'Sullivan MG, Cao Q, Chu H, Lipscomb JD, Atkins WM, Gupta K, Kelekar A, Blair IA, Capdevila JH, Falck JR, Sligar SG, Poulos TL, Georg GI, Ambrose E, Potter DA Cell Chem Biol. 2017 Oct 19;24(10):1259-1275.e6. doi:, 10.1016/j.chembiol.2017.08.009. Epub 2017 Sep 14. PMID:28919040^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.