Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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. Guo et al. discover inhibition of CYP3A4 AA epoxygenase by biguanides, thereby demonstrating convergence between eicosanoid activity in mitochondria and biguanide action in cancer, opening a new avenue for cancer drug discovery.

Original languageEnglish (US)
Pages (from-to)1259-1275.e6
JournalCell Chemical Biology
Volume24
Issue number10
DOIs
StatePublished - Oct 19 2017

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Biguanides
Cytochrome P-450 CYP3A
Mitochondria
Heme
Cytochrome P-450 Enzyme System
Cells
Neoplasms
Metformin
Tumors
AMP-Activated Protein Kinases
Eicosanoids
Drug Discovery
Breast Neoplasms
Biosynthesis
Autophagy
Medical problems
Electron Transport
Mixed Function Oxygenases
Arachidonic Acid
Catalytic Domain

Keywords

  • CYP3A4
  • autophagy
  • biguanide
  • breast cancer
  • cytochrome P450
  • electron transport chain
  • epoxyeicosatrienoic acid
  • hexyl-benzyl-biguanide
  • metformin
  • mitochondria

Cite this

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

In: Cell Chemical Biology, Vol. 24, No. 10, 19.10.2017, p. 1259-1275.e6.

Research output: Contribution to journalArticle

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, Galván, A, Bae, YK, Wulfkuhle, JD, Gallagher, RI, Petricoin, EF, 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 2017, 'Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria', Cell Chemical Biology, vol. 24, no. 10, pp. 1259-1275.e6. https://doi.org/10.1016/j.chembiol.2017.08.009
Guo Z, Sevrioukova IF, Denisov IG, Zhang X, Chiu TL, Thomas DG et al. Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria. Cell Chemical Biology. 2017 Oct 19;24(10):1259-1275.e6. https://doi.org/10.1016/j.chembiol.2017.08.009
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, 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. / Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria. In: Cell Chemical Biology. 2017 ; Vol. 24, No. 10. pp. 1259-1275.e6.
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AU - Guo, Zhijun

AU - Sevrioukova, Irina F.

AU - Denisov, Ilia G.

AU - Zhang, Xia

AU - Chiu, Ting Lan

AU - Thomas, Dafydd G.

AU - Hanse, Eric A.

AU - Cuellar, Rebecca A.D.

AU - Grinkova, Yelena V.

AU - Langenfeld, Vanessa Wankhede

AU - Swedien, Daniel S.

AU - Stamschror, Justin D.

AU - Alvarez, Juan

AU - Luna, Fernando

AU - Galván, Adela

AU - Bae, Young Kyung

AU - Wulfkuhle, Julia D.

AU - Gallagher, Rosa I.

AU - Petricoin, Emanuel F.

AU - Norris, Beverly

AU - Flory, Craig M.

AU - Schumacher, Robert J.

AU - O'Sullivan, M. Gerard

AU - Cao, Qing

AU - Chu, Haitao

AU - Lipscomb, John D.

AU - Atkins, William M.

AU - Gupta, Kalpna

AU - Kelekar, Ameeta

AU - Blair, Ian A.

AU - Capdevila, Jorge H.

AU - Falck, John R.

AU - Sligar, Stephen G.

AU - Poulos, Thomas L.

AU - Georg, Gunda I.

AU - Ambrose, Elizabeth

AU - Potter, David A.

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KW - CYP3A4

KW - autophagy

KW - biguanide

KW - breast cancer

KW - cytochrome P450

KW - electron transport chain

KW - epoxyeicosatrienoic acid

KW - hexyl-benzyl-biguanide

KW - metformin

KW - mitochondria

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