Central role of lactate and proton in cancer cell resistance to glucose deprivation and its clinical translation

Targeting common weaknesses of cancer is an important strategy for cancer therapy. Glucose is a nutrient that maintains essential cellular metabolism, supporting cancer cell survival, growth and proliferation. Depriving glucose rapidly kills cancer cells. Most cancer cells possess a feature called Warburg effect, which refers to that cancer cells even with ample oxygen exhibit an exceptionally high glycolysis rate and convert most incoming glucose to lactate. Although it is recognized that Warburg effect confers growth advantage to cancer cells when glucose supply is sufficient, this feature could be considered as a fatal weakness of cancer cells when glucose supply is a problem. As glucose supply in many solid tumors is poor, and as most cancer cells have exceptionally high glycolytic capacity, maximizing cancer cell glycolysis rate would possibly exhaust intratumoral glucose, leading cancer cell to death. Lactate and proton are two common factors in solid tumors, they jointly protect cancer cells against glucose deprivation, and they are also powerful regulators dictating glucose metabolic phenotypes of cancer cells. Disrupting the joint action of lactate and proton, for example, by means of bicarbonate infusion into tumor, could maximize cancer cell glycolytic rate to rapidly use up glucose, expose their vulnerability to glucose deprivation and ultimately kill cancer cells. A pilot clinical study demonstrated that this approach achieved a remarkable improvement in local control of large and huge hepatocellular carcinoma.