Abstract
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.
Highlights
Lung cancer is the second most commonly occurring cancer, with the highest mortality rate worldwide, accounting for 2.2 million cases and 1.8 million deaths in 2020
This study aimed to investigate the impact of DCA on non-small cell lung cancer (NSCLC) cellular viability, colony growth, and cellular migration and invasion in vitro, in addition to tumor growth, metastasis and toxicity in vivo
We investigated the effect of DCA in combination therapies with chemotherapy and the first generation of EGFR tyrosine kinase inhibitors (EGFR-TKi)
Summary
Lung cancer is the second most commonly occurring cancer, with the highest mortality rate worldwide, accounting for 2.2 million cases and 1.8 million deaths in 2020. Most lung cancer cases are NSCLC, accounting for 80–85% of all lung cancer cases [2]. The development of targeted and immunotherapies has revolutionized the treatment of NSCLC. Side effects, resistance and efficacity in a small therapeutically sensitive group of patients create inequalities in access to such agents [3,4,5]. This underscores the need for safer and more efficacious agents
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