Harnessing Lactate Metabolism for Radiosensitization

Abstract

Cancer cells rewire their metabolism to promote cell proliferation, invasion, and metastasis. Alterations in the lactate pathway have been characterized in diverse cancers, correlate with outcomes, and lead to many downstream effects, including decreasing oxidative stress, promoting an immunosuppressive tumor microenvironment, lipid synthesis, and building chemo- or radio-resistance. Radiotherapy is a key modality of treatment for many cancers and approximately 50% of patients with cancer will receive radiation for cure or palliation; thus, overcoming radio-resistance is important for improving outcomes. Growing research suggests that important molecular controls of the lactate pathway may serve as novel therapeutic targets and in particular, radiosensitizers. In this mini-review, we will provide an overview of lactate metabolism in cancer, discuss three important contributors to lactate metabolism (lactate dehydrogenase, monocarboxylate transporters, and mitochondrial pyruvate carrier), and present data that inhibition of these three pathways can lead to radiosensitization. Future research is needed to further understand critical regulators of lactate metabolism and explore clinical safety and efficacy of inhibitors of lactate dehydrogenase, monocarboxylate transporters, and mitochondrial pyruvate carrier alone and in combination with radiation.

Keywords: Warburg phenomenon; lactate metabolism; radiation therapy; radiosensitization; synergistic effects.

Figure 1

Schematic of the lactate pathway and illustration of novel therapeutic strategies that have been shown to decrease tumor growth in preclinical studies. Drugs discussed in this review are presented in red and are shown by their putative target of action. ECT, electron transport chain; G-6-P, glucose-6-phosphate; GLUT, glucose transporter; cLDH, cytosolic lactate dehydrogenase; mLDH, mitochondrial lactate dehydrogenase; MCT1, monocarboxylate transporter 1; MCT4, monocarboxylate transporter 4; MPC, mitochondrial pyruvate carrier; NAD+, nicotinamide adenine dinucleotide (oxidized); NADH, nicotinamide adenine dinucleotide (reduced); PEP, phosphoenolpyruvate; PDH, pyruvate dehydrogenase.