Dichloroacetate as a novel pharmaceutical treatment for cancer-related fatigue in melanoma

Xinyi Zhang, Won D. Lee, Brooks P. Leitner, Wanling Zhu, Andin Fosam, Zongyu Li, Rafael C. Gaspar, Alexandra A. Halberstam, Briana Robles, Joshua D. Rabinowitz, Rachel J. Perry

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Cancer-related fatigue (CRF) is one of the most common complications in patients with multiple cancer types and severely affects patients’ quality of life. However, there have only been single symptom-relieving adjuvant therapies but no effective pharmaceutical treatment for the CRF syndrome. Dichloroacetate (DCA), a small molecule inhibitor of pyruvate dehydrogenase kinase, has been tested as a potential therapy to slow tumor growth, based largely on its effects in vitro to halt cell division. We found that although DCA did not affect rates of tumor growth or the efficacy of standard cancer treatment (immunotherapy and chemotherapy) in two murine cancer models, DCA preserved physical function in mice with late-stage tumors by reducing circulating lactate concentrations. In vivo liquid chromatography-mass spectrometry/mass spectrometry studies suggest that DCA treatment may preserve membrane potential, postpone proteolysis, and relieve oxidative stress in muscles of tumor-bearing mice. In all, this study provides evidence for DCA as a novel pharmaceutical treatment to maintain physical function and motivation in murine models of CRF. NEW & NOTEWORTHY We identify a new metabolic target for cancer-related fatigue, dichloroacetate (DCA). They demonstrate that in mice, DCA preserves physical function and protects against the detrimental effects of cancer treatment by reducing cancer-induced increases in circulating lactate. As DCA is already FDA approved for another indication, these results could be rapidly translated to clinical trials for this condition for which no pharmaceutical therapies exist beyond symptom management.

Original languageEnglish (US)
Pages (from-to)E363-E375
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume325
Issue number4
DOIs
StatePublished - Oct 2023

All Science Journal Classification (ASJC) codes

  • General Medicine

Keywords

  • cancer-related fatigue
  • physical function
  • skeletal muscle

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