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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.
Afiliação
  • Guo Z; Department of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • Sevrioukova IF; Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA.
  • Denisov IG; Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • Zhang X; Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
  • Chiu TL; Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
  • Thomas DG; Department of Pathology and Cancer Center, University of Michigan, Ann Arbor, MN, USA.
  • Hanse EA; Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • Cuellar RAD; Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
  • Grinkova YV; Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • Langenfeld VW; Department of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • Swedien DS; Department of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • Stamschror JD; Department of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • Alvarez J; Department of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • Luna F; Department of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Unidad de Investigacion Biomedica en Cancer, Instituto Nacional de Cancerologia-Instituto de Investigaciones Biomedicas, UNAM, Mexico, Mexico.
  • Galván A; Department of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Unidad de Investigacion Biomedica en Cancer, Instituto Nacional de Cancerologia-Instituto de Investigaciones Biomedicas, UNAM, Mexico, Mexico.
  • Bae YK; Department of Pathology, Yeungnam University, Daegu, Korea.
  • Wulfkuhle JD; Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA, USA.
  • Gallagher RI; Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA, USA.
  • Petricoin EF; Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA, USA.
  • Norris B; Center for Translational Medicine, University of Minnesota, Minneapolis, MN, USA.
  • Flory CM; Center for Translational Medicine, University of Minnesota, Minneapolis, MN, USA.
  • Schumacher RJ; Center for Translational Medicine, University of Minnesota, Minneapolis, MN, USA.
  • O'Sullivan MG; College of Veterinary Medicine and Masonic Cancer Center, University of Minnesota, St. Paul, MN, USA.
  • Cao Q; Division of Biostatistics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • Chu H; Division of Biostatistics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • Lipscomb JD; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
  • Atkins WM; Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA.
  • Gupta K; Department of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • Kelekar A; Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • Blair IA; Department of Pharmacology, Center for Cancer Pharmacology and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
  • Capdevila JH; Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University, Nashville, TN, USA.
  • Falck JR; Departments of Biochemistry and Pharmacology, University of Texas Southwestern, Dallas, TX, USA.
  • Sligar SG; Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • Poulos TL; Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA.
  • Georg GI; Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
  • Ambrose E; Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
  • Potter DA; Department of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. Electronic address: dapotter@umn.edu.
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 / Citocromo P-450 CYP3A / Heme / Mitocôndrias Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Biguanidas / Citocromo P-450 CYP3A / Heme / Mitocôndrias Idioma: En Ano de publicação: 2017 Tipo de documento: Article