1] Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK [2] Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
Br J Cancer. 2014 Jul 15;111(2):375-85. doi: 10.1038/bjc.2014.281. Epub 2014 Jun 3.
Dichloroacetate (DCA) has been found to have antitumour properties.
We investigated the cellular and metabolic responses to DCA treatment and recovery in human colorectal (HT29, HCT116 WT and HCT116 Bax-ko), prostate carcinoma cells (PC3) and HT29 xenografts by flow cytometry, western blotting, electron microscopy, (1)H and hyperpolarised (13)C-magnetic resonance spectroscopy.
Increased expression of the autophagy markers LC3B II was observed following DCA treatment both in vitro and in vivo. We observed increased production of reactive oxygen species (ROS) and mTOR inhibition (decreased pS6 ribosomal protein and p4E-BP1 expression) as well as increased expression of MCT1 following DCA treatment. Steady-state lactate excretion and the apparent hyperpolarised [1-(13)C] pyruvate-to-lactate exchange rate (k(PL)) were decreased in DCA-treated cells, along with increased NAD(+)/NADH ratios and NAD(+). Steady-state lactate excretion and k(PL) returned to, or exceeded, control levels in cells recovered from DCA treatment, accompanied by increased NAD(+) and NADH. Reduced k(PL) with DCA treatment was found in HT29 tumour xenografts in vivo.
DCA induces autophagy in cancer cells accompanied by ROS production and mTOR inhibition, reduced lactate excretion, reduced k(PL) and increased NAD(+)/NADH ratio. The observed cellular and metabolic changes recover on cessation of treatment.
二氯乙酸（DCA）已被发现具有抗肿瘤特性。
我们通过流式细胞术、Western blot、电子显微镜、（1）H 和高极化（13）C 磁共振波谱研究了 DCA 处理和恢复后人类结直肠（HT29、HCT116 WT 和 HCT116 Bax-ko）、前列腺癌细胞（PC3）和 HT29 异种移植物的细胞和代谢反应。
在体外和体内，DCA 处理后均观察到自噬标记物 LC3B II 的表达增加。我们观察到活性氧（ROS）产生增加和 mTOR 抑制（pS6 核糖体蛋白和 p4E-BP1 表达减少），以及 DCA 处理后 MCT1 的表达增加。DCA 处理的细胞中稳态乳酸排泄和明显高极化 [1-（13）C] 丙酮酸到乳酸交换率（k（PL））降低，同时 NAD（+）/NADH 比值和 NAD（+）增加。从 DCA 处理中恢复的细胞中，稳态乳酸排泄和 k（PL）恢复到或超过对照水平，同时 NAD（+）和 NADH 增加。体内 HT29 肿瘤异种移植物中发现 DCA 处理时 k（PL）降低。
DCA 在癌细胞中诱导自噬，伴有 ROS 产生和 mTOR 抑制、乳酸排泄减少、k（PL）降低和 NAD（+）/NADH 比值增加。停止治疗后观察到细胞和代谢变化恢复。
