Altered metabolic pathways in cancer such as exacerbated glycolytic flux and increased glutamine metabolism are promising targets for anti-cancer therapies. While commonly observed in glycolytic tumors, extracellular acidosis has never been considered as a potential modulator of anti-metabolic drug activity such as dichloroacetate (DCA). Using cancer cells from various origins selected for their ability to proliferate under acidic conditions, we found that DCA exerts greater inhibitory effects on the growth of these acid-adapted cells than in parental cells. Moreover, daily DCA administration to mice led to a significant decrease in tumor growth from acid-adapted cells but not from parental cells. 13C-tracer studies revealed that DCA induced a double metabolic shift, diminishing glycolysis and increasing intracellular glutamine in acid-adapted cells. As a consequence, DCA reduced the pentose phosphate pathway activity more extensively and increased apoptosis in acid-adapted cells. Finally, the combination of DCA with a glutaminase inhibitor significantly enhanced the cytotoxic effects of DCA. Overall, the interplay between acidosis and DCA exposure leads to metabolic reprogramming that considerably alters cellular fitness.

中文翻译：

---

酸中毒诱导的肿瘤细胞代谢重编程增强了PDK抑制剂二氯乙酸盐的抗增殖活性。

癌症中代谢途径的改变，例如加剧的糖酵解通量和谷氨酰胺代谢的增加，是抗癌治疗的有希望的目标。尽管通常在糖酵解性肿瘤中观察到，但胞外酸中毒从未被认为是抗代谢药物活性（如二氯乙酸盐（DCA））的潜在调节剂。使用从各种来源选择的癌细胞来选择其在酸性条件下的增殖能力，我们发现DCA对这些酸适应细胞的生长比亲代细胞具有更大的抑制作用。而且，每天向小鼠施用DCA会导致来自酸适应细胞的肿瘤生长显着下降，而不是来自亲代细胞的肿瘤生长显着下降。13C示踪剂研究表明DCA引起了新陈代谢的双重转变，减少糖酵解并增加酸适应细胞中的细胞内谷氨酰胺。结果，DCA更广泛地降低了戊糖磷酸途径的活性，并增加了酸适应细胞的凋亡。最后，DCA与谷氨酰胺酶抑制剂的组合显着增强了DCA的细胞毒性作用。总体而言，酸中毒和DCA暴露之间的相互作用导致代谢重编程，从而大大改变了细胞的适应性。