TY - JOUR
T1 - Dichloroacetate as a novel pharmaceutical treatment for cancer-related fatigue in melanoma
AU - Zhang, Xinyi
AU - Lee, Won D.
AU - Leitner, Brooks P.
AU - Zhu, Wanling
AU - Fosam, Andin
AU - Li, Zongyu
AU - Gaspar, Rafael C.
AU - Halberstam, Alexandra A.
AU - Robles, Briana
AU - Rabinowitz, Joshua D.
AU - Perry, Rachel J.
N1 - Publisher Copyright:
Copyright © 2023 the American Physiological Society.
PY - 2023/10
Y1 - 2023/10
N2 - 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.
AB - 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.
KW - cancer-related fatigue
KW - physical function
KW - skeletal muscle
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U2 - 10.1152/ajpendo.00105.2023
DO - 10.1152/ajpendo.00105.2023
M3 - Article
C2 - 37646579
AN - SCOPUS:85174080050
SN - 0193-1849
VL - 325
SP - E363-E375
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 4
ER -