Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, Al-Ain 17666, United Arab Emirates.
Department of Medicine, College of Medicine & Health Sciences, United Arab Emirates University, Al-Ain 17666, United Arab Emirates.
Int J Mol Sci. 2021 Nov 21;22(22):12553. doi: 10.3390/ijms222212553.
Metabolic reprogramming has been recognized as an essential emerging cancer hallmark. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been reported to have anti-cancer effects by reversing tumor-associated glycolysis. This study was performed to explore the anti-cancer potential of DCA in lung cancer alone and in combination with chemo- and targeted therapies using two non-small cell lung cancer (NSCLC) cell lines, namely, A549 and LNM35. DCA markedly caused a concentration- and time-dependent decrease in the viability and colony growth of A549 and LNM35 cells in vitro. DCA also reduced the growth of tumor xenografts in both a chick embryo chorioallantoic membrane and nude mice models in vivo. Furthermore, DCA decreased the angiogenic capacity of human umbilical vein endothelial cells in vitro. On the other hand, DCA did not inhibit the in vitro cellular migration and invasion and the in vivo incidence and growth of axillary lymph nodes metastases in nude mice. Treatment with DCA did not show any toxicity in chick embryos and nude mice. Finally, we demonstrated that DCA significantly enhanced the anti-cancer effect of cisplatin in LNM35. In addition, the combination of DCA with gefitinib or erlotinib leads to additive effects on the inhibition of LNM35 colony growth after seven days of treatment and to synergistic effects on the inhibition of A549 colony growth after 14 days of treatment. Collectively, this study demonstrates that DCA is a safe and promising therapeutic agent for lung cancer.
代谢重编程已被认为是癌症的一个基本特征。二氯乙酸（DCA）是丙酮酸脱氢酶激酶（PDK）的抑制剂，通过逆转肿瘤相关的糖酵解，已被报道具有抗癌作用。本研究旨在探讨 DCA 在单独使用和联合化疗和靶向治疗的情况下对肺癌的抗癌潜力，使用两种非小细胞肺癌（NSCLC）细胞系 A549 和 LNM35 进行研究。DCA 明显导致 A549 和 LNM35 细胞在体外的活力和集落生长呈浓度和时间依赖性下降。DCA 还降低了鸡胚绒毛尿囊膜和裸鼠体内肿瘤异种移植物的生长。此外，DCA 降低了人脐静脉内皮细胞的体外血管生成能力。另一方面，DCA 并未抑制裸鼠体内细胞迁移和侵袭以及腋窝淋巴结转移的发生率和生长。DCA 治疗在鸡胚和裸鼠中均未显示出任何毒性。最后，我们证明 DCA 显著增强了顺铂对 LNM35 的抗癌作用。此外，DCA 与吉非替尼或厄洛替尼联合使用，在治疗 7 天后对 LNM35 集落生长的抑制作用具有相加作用，在治疗 14 天后对 A549 集落生长的抑制作用具有协同作用。总之，这项研究表明 DCA 是一种安全且有前景的肺癌治疗药物。
