Cell Reports
Volume 30, Issue 6, 11 February 2020, Pages 1798-1810.e4
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Article
Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy

https://doi.org/10.1016/j.celrep.2020.01.039Get rights and content
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Highlights

  • Specific LDH inhibition in vivo reduces growth rate of glycolytic tumors

  • Depth and duration of tumor LDH inhibition can be monitored in real time by HP-MRSI

  • LDH inhibition in vivo redirects pyruvate to support oxidative phosphorylation

  • Inhibiting mitochondrial complex 1 and LDH enhances durability of anti-tumor response

Summary

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.

Keywords

lactate dehydrogenase
pyruvate metabolism
metabolic flux
cancer
metabolic imaging
hyperpolarized magnetic resonance spectroscopic imaging

Cited by (0)

12

Present address: Kyoto University Hospital, Department of Gastrointestinal Surgery, Kyoto, 606-8507 Japan

13

Present address: University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA

14

Present address: Veralox Therapeutics Inc., Frederick, MD 21704, USA

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Lead Contact