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

  title={Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.},
  author={Zhijun Guo and Irina F Sevrioukova and Ilia G Denisov and Xia Zhang and Ting-Lan Chiu and Dafydd Gareth Thomas and Eric Allan Hanse and Rebecca A D Cuellar and Yelena V. Grinkova and Vanessa Wankhede Langenfeld and Daniel S. Swedien and Justin D. Stamschror and Juan D. Ortega Alvarez and Fernando Gabriel Luna and Adela Hern{\'a}ndez Galv{\'a}n and Young Kyung Bae and Julia D. Wulfkuhle and Rosa I. Gallagher and Emanual F. Petricoin and Beverly J. Norris and Craig M. Flory and Robert J. Schumacher and Michael G O'Sullivan and Qing Cao and Haitao Chu and John D Lipscomb and William M Atkins and Kalpna Gupta and Ameeta Kelekar and Ian A Blair and J. Capdevila and John R Falck and Stephen G Sligar and Thomas L Poulos and Gunda I. Georg and Elizabeth Ambrose and David A. Potter},
  journal={Cell chemical biology},
  volume={24 10},
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… CONTINUE READING
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