title: Effective inhibition of nasopharyngeal carcinoma in vitro and in vivo by targeting glycolysis with oxamate.
abstract: Elevated aerobic glycolysis in cancer cells (Warburg effect) has been observed in many tumor types including nasopharyngeal carcinoma (NPC), which can often be detected clinically using FDG-PET. However, the role of glycolysis in supporting the growth of NPC cells and its therapeutic implications still remain to be investigated. In the present study, we showed that the LDH inhibitor oxamate significantly suppressed NPC cell proliferation in vitro and tumor growth in vivo, yet exhibited minimum toxicity to normal nasopharyngeal epithelial cells in vitro and was well tolerated in mice. Moreover, oxamate exhibited cytotoxic effect in NPC cells under hypoxia. Mechanistic study showed that oxamate significantly inhibited LDH activity, leading to a substantial decrease in glucose uptake and lactate production. Combination of oxamate with a mitochondrial respiratory complex I inhibitor resulted in a significant depletion of cellular ATP and a synergistic killing of cancer cells. Our results suggest that inhibition of glycolysis by oxamate is an effective therapeutic strategy for treatment of NPC and that combination of this compound with mitochondrial-targeted agents may improve the therapeutic activity.
authors: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510275, P.R. China.
authors: Xiaobing
authors: X
authors: Li
authors: Wenhua
authors: W
authors: Lu
authors: Yumin
authors: Y
authors: Hu
authors: Shijun
authors: S
authors: Wen
authors: Chaonan
authors: C
authors: Qian
authors: Wenjing
authors: W
authors: Wu
authors: Peng
authors: P
authors: Huang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002277:Carcinoma; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010072:Oxamic Acid / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D005947:Glucose; D010072:Oxamic Acid