Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States.
Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States.
Am J Physiol Endocrinol Metab. 2023 Oct 1;325(4):E363-E375. doi: 10.1152/ajpendo.00105.2023. Epub 2023 Aug 30.
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. 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.
癌症相关性乏力（CRF）是多种癌症患者最常见的并发症之一，严重影响患者的生活质量。然而，对于 CRF 综合征，仅有单一的缓解症状的辅助治疗，而没有有效的药物治疗。二氯乙酸（DCA）是丙酮酸脱氢酶激酶的小分子抑制剂，已被测试为一种潜在的治疗方法，以减缓肿瘤生长，主要基于其在体外停止细胞分裂的作用。我们发现，尽管 DCA 并没有影响两种小鼠癌症模型中的肿瘤生长速度或标准癌症治疗（免疫疗法和化学疗法）的疗效，但 DCA 通过降低循环乳酸盐浓度，在晚期肿瘤小鼠中保持了身体功能。体内液相色谱-质谱/质谱研究表明，DCA 治疗可能在荷瘤小鼠的肌肉中维持膜电位、推迟蛋白水解并缓解氧化应激。总之，这项研究为 DCA 作为一种治疗癌症相关性乏力的新型药物治疗方法提供了证据。我们确定了癌症相关性乏力的一个新的代谢靶点，二氯乙酸（DCA）。他们表明，在小鼠中，DCA 通过降低癌症引起的循环乳酸盐增加来保持身体功能并预防癌症治疗的有害影响。由于 DCA 已经获得 FDA 批准用于另一种适应症，因此这些结果可以快速转化为临床试验，对于这种没有药物治疗的疾病，除了症状管理之外，还需要进行药物治疗。
