ArticleCell chemical biology2017
Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.
Erratum issuedOpen access · bronzeAbstract read
In one paragraph
Article in Cell chemical biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 25 papers.
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0cells of the map it votes in
25citing papers in PubMed
3.1field-weighted citation impact, top 9% of its field
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
25 citing papers in PubMed, 51 citations in OpenAlex.
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- The Effect of Metformin and Hydrochlorothiazide on Cytochrome P450 3A4 Metabolism of Ivermectin: Insights from In Silico Experimentation.International journal of molecular sciences · 2024Article
- Chemical imaging unveils mitochondria as the major site of medicinal biguanide accumulation within cells.Heliyon · 2024Article
- Harnessing Oxylipins and Inflammation Modulation for Prevention and Treatment of Colorectal Cancer.International journal of molecular sciences · 2024Review
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- Longitudinal dynamics of the tumor hypoxia response: From enzyme activity to biological phenotype.Science advances · 2023Review
- Novel Anti-Cancer Products Targeting AMPK: Natural Herbal Medicine against Breast Cancer.Molecules (Basel, Switzerland) · 2023Review
- The Role of CYP3A in Health and Disease.Biomedicines · 2022Review
- Metabolic Action of Metformin.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Study on the Characteristics of Small-Molecule Kinase Inhibitors-Related Drug-Induced Liver Injury.Frontiers in pharmacology · 2022Article
- Drug-Metabolizing Cytochrome P450 Enzymes Have Multifarious Influences on Treatment Outcomes.Clinical pharmacokinetics · 2021Review
- Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets.Signal transduction and targeted therapy · 2021Review
- Cellular and Molecular Mechanisms of Metformin Action.Endocrine reviews · 2021Review
- Dual-Functional Peptide Driven Liposome Codelivery System for Efficient Treatment of Doxorubicin-Resistant Breast Cancer.Drug design, development and therapy · 2021Article
Corrections and comments
- Erratum issued
Authors and funding
37 authors at 12 institutions in 3 countries.
Zhijun GuoDepartment of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Irina F SevrioukovaDepartment of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA.
Ilia G DenisovDepartment of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
Xia ZhangDepartment of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
Ting-Lan ChiuDepartment of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
Dafydd G ThomasDepartment of Pathology and Cancer Center, University of Michigan, Ann Arbor, MN, USA.
Eric A HanseDepartment of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Rebecca A D CuellarDepartment of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
Yelena V GrinkovaDepartment of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
Vanessa Wankhede LangenfeldDepartment of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Daniel S SwedienDepartment of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Justin D StamschrorDepartment of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Juan AlvarezDepartment of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Fernando LunaDepartment 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.
Adela GalvánDepartment 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.
Young Kyung BaeDepartment of Pathology, Yeungnam University, Daegu, Korea.
Julia D WulfkuhleCenter for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA, USA.
Rosa I GallagherCenter for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA, USA.
Emanuel F PetricoinCenter for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA, USA.
Beverly NorrisCenter for Translational Medicine, University of Minnesota, Minneapolis, MN, USA.
Craig M FloryCenter for Translational Medicine, University of Minnesota, Minneapolis, MN, USA.
Robert J SchumacherCenter for Translational Medicine, University of Minnesota, Minneapolis, MN, USA.
M Gerard O'SullivanCollege of Veterinary Medicine and Masonic Cancer Center, University of Minnesota, St. Paul, MN, USA.
Qing CaoDivision of Biostatistics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Haitao ChuDivision of Biostatistics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
John D LipscombDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
William M AtkinsDepartment of Medicinal Chemistry, University of Washington, Seattle, WA, USA.
Kalpna GuptaDepartment of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Ameeta KelekarDepartment of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Ian A BlairDepartment of Pharmacology, Center for Cancer Pharmacology and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Jorge H CapdevilaDepartment of Medicine, Division of Nephrology and Hypertension, Vanderbilt University, Nashville, TN, USA.
John R FalckDepartments of Biochemistry and Pharmacology, University of Texas Southwestern, Dallas, TX, USA.
Stephen G SligarDepartment of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
Thomas L PoulosDepartment of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA.
Gunda I GeorgDepartment of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
Elizabeth AmbroseDepartment of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
David A PotterDepartment of Medicine Hematology, Oncology and Transplantation Division and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. Electronic address: dapotter@umn.edu.
University of Minnesota · USUniversity of Minnesota Medical Center · USGeorge Mason University · USUniversity of Illinois Urbana-Champaign · USInstituto Nacional de Cancerología · MXUniversity of California, Irvine · USAbramson Cancer CenterThe University of Texas Southwestern Medical Center · USUniversity of Michigan–Ann Arbor · USUniversity of Washington · USVanderbilt University · USYeungnam University · KR
Funding
UNIVERSITY OF PENNSYLVANIA CAN CTR SUPPORT GRANTP30CA016520 · NCI · UNIVERSITY OF PENNSYLVANIA · PI Robert H. Vonderheide · 1985 to 2026
$222.3MWomen's CancerP30CA077598 · NCI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI Jeffrey S. Miller · 1998 to 2026
$100.4MMayo Clinic Center for Translational Science ActivitiesUL1TR000135 · NCATS · MAYO CLINIC ROCHESTER · PI KHOSLA, SUNDEEP · 2012 to 2015
$41.2MTranslational Research Support CoreP30ES013508 · NIEHS · UNIVERSITY OF PENNSYLVANIA · PI Trevor M Penning · 2006 to 2026
$35.3MUniversity of Minnesota Clinical and Translational Science Institute (UMN CTSI)UL1TR000114 · NCATS · UNIVERSITY OF MINNESOTA · PI BLAZAR, BRUCE R · 2012 to 2015
$35.0MTRANSPORT EFFECTS OF ARACHIDONATE METABOLITES IN PERFUSED TUBULEP01DK038226 · NIDDK · VANDERBILT UNIVERSITY MEDICAL CENTER · PI BROWN, NANCY J. · 1986 to 2015
$22.1MPharmacological Sciences SupplementT32GM007750 · NIGMS · UNIVERSITY OF WASHINGTON · PI ATKINS, WILLIAM M · 1985 to 2023
$12.6MCannabinoid-based therapy and approaches to quantify pain in sickle cell diseaseU01HL117664 · NHLBI · UNIVERSITY OF MINNESOTA · PI GUPTA, KALPNA · 2013 to 2018
$9.6MNanoscale Approaches to Understanding Membrane Protein FunctionR35GM118145 · NIGMS · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · PI STEPHEN G. SLIGAR · 2016 to 2026
$7.5MSTRUCTURAL STUDIES ON NITRIC OXIDE SYNTHASER01GM057353 · NIGMS · UNIVERSITY OF CALIFORNIA-IRVINE · PI POULOS, THOMAS L · 1998 to 2018
$6.8MToxicological importance of CYP3A4 catalysis and inhibitionR01ES025767 · NIEHS · UNIVERSITY OF CALIFORNIA-IRVINE · PI SEVRIOUKOVA, IRINA F · 2016 to 2025
$4.0MSummer Research Training at the University of Minnesota Medical SchoolR25HL088728 · NHLBI · UNIVERSITY OF MINNESOTA · PI COLIN R CAMPBELL, Dang Hai Nguyen · 2007 to 2026
$2.9MNCATS NIH HHS UL1 TR000114NCATS NIH HHS UL1 TR000135NCI NIH HHS F31 CA177119NCI NIH HHS P30 CA016520NCI NIH HHS P30 CA077598NCI NIH HHS R01 CA113570NCI NIH HHS R01 CA157971NHLBI NIH HHS R25 HL088728NHLBI NIH HHS U01 HL117664NIDDK NIH HHS P01 DK038226NIEHS NIH HHS P30 ES013508NIEHS NIH HHS R01 ES025767NIGMS NIH HHS R01 GM037922NIGMS NIH HHS R01 GM057353NIGMS NIH HHS R01 GM110790NIGMS NIH HHS R35 GM118030NIGMS NIH HHS R35 GM118145
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
Indexed as
AMP-Activated Protein KinasesAnimalsBiguanidesBreast NeoplasmsCatalytic DomainCell RespirationCytochrome P-450 CYP3AEstrogen Receptor alphaFemaleGene Expression Regulation, NeoplasticGene SilencingHemeHumansMCF-7 CellsMembrane Potential, MitochondrialMiceAMP-Activated Protein KinasesBiguanidesCytochrome P-450 CYP3AEstrogen Receptor alphaHemeautophagybiguanidebreast cancerCYP3A4cytochrome P450electron transport chainepoxyeicosatrienoic acidhexyl-benzyl-biguanidemetforminmitochondria
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.