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

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.

Keywords: cancer-related fatigue; physical function; skeletal muscle.

Graphical abstract

Figure 1.

DCA has no effect on YUMMER1.7 tumor growth but preserves physical performance in mice with advanced-stage tumors. A: YUMMER1.7 tumor volume. DCA treatment started on day 1 after tumor injection (n = 8). B: grip strength (n = 8). C: maximal running speed (n = 10). D: peak oxygen uptake (V̇o_2peak) before tumor injection, 1 wk after tumor injection and 3 wk after tumor injection (n = 5). E: daily voluntary running distance in home cages containing ad libitum running wheels or immovable wheels (n = 8). Tumor cells were injected after 6-day acclimation to the cages. F: forced swimming time at the early and late stages of tumor progression (n = 10). In all panels, SE is shown; n represents number of animals; *P < 0.05, ***P < 0.001, ****P < 0.0001). DCA, dichloroacetate.

Figure 2.

DCA neither alters food/water intake nor improves systemic inflammation or anemia. Basal respiratory exchange ratio (A), ad libitum food (B), and water intake (C) of control and DCA-treated mice with early- and late-stage tumors, measured using metabolic cages (n = 8). D: plasma concentrations of inflammatory cytokines (n = 6). E: white blood cell counts (WBC, white blood cell; NE, neutrophil; LY, lymphocyte; MO, monocyte; EO, eosinophil). F: red blood cell number in untreated and DCA-treated tumor-bearing mice (n = 8). SE is shown; n represents number of animals; **P < 0.01, ****P < 0.0001. DCA, dichloroacetate.

Figure 3.

DCA preserves muscle mitochondrial membrane potential and enhances metabolic flux through TCA cycle. A: tracer labeling in glycolysis with [U-¹³C₆]-glucose as tracer. Adapted from “glycolysis,” by BioRender.com (2022), retrieved from https://app.biorender.com/biorender-templates. ¹³C enrichment of glycolytic intermediates (B) and fractional contribution of glucose to pyruvate (a readout of glycolysis) in muscle tissue (C). D: tracer labeling scheme reflecting the first turn of the TCA cycle infused with [U-¹³C₆] glucose (n = 5). Adapted from “Kreb’s [sic] Cycle,” by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates. Enrichment of TCA cycle intermediates (E) and fractional contribution of m + 3 pyruvate to m + 2 citrate/isocitrate in muscle tissue from [U-¹³C₆] glucose-infused tumor-bearing mice (F). Enrichment of glycolytic intermediates (G), fractional contribution of pyruvate to the TCA cycle (H), and TCA cycle intermediates in skeletal muscle (I) obtained from tumor-bearing mice gavaged with [U-¹³C₆] glucose (n = 5). The mean is presented with SE; n represents number of animals; *P < 0.05, DCA, dichloroacetate.

Figure 4.

DCA preserves physical function by reducing circulating lactate concentration in tumor-bearing mice. A: plasma lactate concentration in tumor-bearing mice (early control n = 10; early DCA n = 11; late control n = 12; late DCA n = 12). B: ¹³C lactate enrichment (m + 3/m + 0) from plasma obtained at 120 min of infusion study using [U-¹³C₆]-glucose as tracer n = 5, with the exception of early DCA for which n = 7. Maximum running speed (C), forced swim time (D), and grip strength (E) measured within 30 min after intraperitoneal sodium lactate injection in DCA-treated tumor-bearing mice with late-stage tumor (for C, D, E, G, and H, n = 5 per group in both groups; for F, n = 4 control and n = 5 lactate). Maximum running speed (F), forced swim time (G), and grip strength (H) measured within 30 min after intraperitoneal sodium lactate injection in healthy control mice. The mean is presented with SE; n represents number of animals *P < 0.05, **P < 0.01. DCA, dichloroacetate.

Figure 5.

DCA relieves immunotherapy-induced CRF in YUMMER1.7 tumor-bearing mice. A: YUMMER1.7 tumor volume on day 18 in mice treated with immunotherapy (anti-PD1 monoclonal antibody) and/or DCA treatment. DCA treatment started on day 1 and immunotherapy started on day 12 after tumor injection. Grip strength (B), maximum running speed (D), and forced swimming time (F) measured at the early and late stage of tumor growth, and the percentage of decreases (C, E, and G), respectively. SE is shown; *P < 0.05, **P < 0.01, ***P < 0.001. n = 5 animals. CRF, cancer-related fatigue; DCA, dichloroacetate.

Figure 6.

DCA relieves chemotherapy-induced CRF in MC38 tumor-bearing mice. A: MC38 tumor volume in chemotherapy (5-fluorouracil) and/or DCA-treated on day 18 after tumor injection. DCA treatment started on day 1 and chemotherapy started on day 13 after tumor injection. Grip strength (B), maximal running speed (D), and forced swimming time (F) measured at the early and late stage, and the percentage of decreases (C, E, and G), respectively. SE is shown; *P < 0.05, **P < 0.01, ****P < 0.0001. n = 5 animals. CRF, cancer-related fatigue; DCA, dichloroacetate.