Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy.

Autor:	Oshima N; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Ishida R; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Kishimoto S; Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Beebe K; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Brender JR; Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Yamamoto K; Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Urban D; Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Rai G; Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Johnson MS; Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Benavides G; Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Squadrito GL; Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Crooks D; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Jackson J; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Joshi A; Department of Cell Biology, University of Geneva, 1211 Geneva 4, Switzerland., Mott BT; Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Shrimp JH; Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Moses MA; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Lee MJ; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Yuno A; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Lee TD; Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Hu X; Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Anderson T; University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA., Kusewitt D; University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA., Hathaway HH; University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA., Jadhav A; Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Picard D; Department of Cell Biology, University of Geneva, 1211 Geneva 4, Switzerland., Trepel JB; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Mitchell JB; Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Stott GM; Leidos Biomedical, Frederick National Laboratory for Cancer Research, Frederick, MD 24060, USA., Moore W; Leidos Biomedical, Frederick National Laboratory for Cancer Research, Frederick, MD 24060, USA., Simeonov A; Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Sklar LA; University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA., Norenberg JP; University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA., Linehan WM; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Maloney DJ; Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Dang CV; Ludwig Institute for Cancer Research, New York, NY 10017, USA; The Wistar Institute, Philadelphia, PA 19104, USA., Waterson AG; Department of Chemistry, Vanderbilt University, Nashville, TN 37240, USA., Hall M; Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Darley-Usmar VM; Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Krishna MC; Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Neckers LM; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: neckersl@mail.nih.gov.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2020 Feb 11; Vol. 30 (6), pp. 1798-1810.e4.
DOI:	10.1016/j.celrep.2020.01.039
Abstrakt:	The reliance of many cancers on aerobic glycolysis has stimulated efforts to develop lactate dehydrogenase (LDH) inhibitors. However, despite significant efforts, LDH inhibitors (LDHi) with sufficient specificity and in vivo activity to determine whether LDH is a feasible drug target are lacking. We describe an LDHi with potent, on-target, in vivo activity. Using hyperpolarized magnetic resonance spectroscopic imaging (HP-MRSI), we demonstrate in vivo LDH inhibition in two glycolytic cancer models, MIA PaCa-2 and HT29, and we correlate depth and duration of LDH inhibition with direct anti-tumor activity. HP-MRSI also reveals a metabolic rewiring that occurs in vivo within 30 min of LDH inhibition, wherein pyruvate in a tumor is redirected toward mitochondrial metabolism. Using HP-MRSI, we show that inhibition of mitochondrial complex 1 rapidly redirects tumor pyruvate toward lactate. Inhibition of both mitochondrial complex 1 and LDH suppresses metabolic plasticity, causing metabolic quiescence in vitro and tumor growth inhibition in vivo. Competing Interests: Declaration of Interests D.U., G.R., B.T.M., X.H., A.J., W.M., A.S., D.J.M., C.V.D., A.G.W., V.M.D.-U., and L.M.N. are inventors on a patent related to this work. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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