Combination of lonidamine with devimistat induces synergistic antitumor effects in lung cancer via multifaceted disruption of cellular energy metabolism.

Abstract

Disrupting energy metabolic pathways has emerged as a promising strategy for cancer therapy including non‑small cell lung cancer (NSCLC). However, the ultimate anticancer effects have not been satisfactory. This is likely because cellular energy metabolism encompasses multiple processes and pathways, and tumor cells can flexibly regulate these processes and pathways to adapt to external disturbances and changes in the microenvironment in order to maintain their growth and proliferation. As a result, current strategies which only target certain aspects of energy metabolism have not achieved commendable results. In the present study, two inhibitors lonidamine and devimistat, each with their own limitations, were combined to treat A549 NSCLC by synergistically interfering with the main aspects of cellular energy metabolism including glycolysis, the tricarboxylic acid cycle and oxidative phosphorylation. The synergistic potency was examined in vitro and in vivo including cytotoxicity, optimal combination doses, colony formation, mitochondrial function, adenosine triphosphate (ATP) and reactive oxygen species (ROS) production, apoptosis and pharmacodynamics in a xenograft mouse model. Moreover, characteristic metabolite levels were measured to elucidate the effects of combination treatment on cellular energy metabolism. The results showed that this combination therapy could synergistically inhibit tumor growth in vitro and in vivo. Furthermore, combining these two metabolic inhibitors could induce the production of ROS, reduce the generation of ATP, impair mitochondrial morphology and function, and ultimately activate apoptosis in tumor cells through metabolic regulation, facilitating antitumor treatment. The findings underscore the necessity and effectiveness of targeting tumor energy metabolism for lung cancer therapy, providing reliable evidence that metabolic therapies can effectively participate in cancer treatment.