Prospects for glycerol-rescued hypoglycemia as a cancer therapy

Most neoplasms are dependent on glucose as their primary fuel, and their ambient glucose levels tend to be rather low owing to wasteful aerobic glycolysis and poor perfusion. Previous attempts to starve tumors by inducing hypoglycemia have foundered on the fact that the CNS and other tissues have high glucose requirements. Burt has proposed that, inasmuch as hypoglycemia-sensitive normal tissues can make efficient use of glycerol, whereas many or most cancers cannot, hypoglycemic cancer therapy may be feasible if glycerol is concurrently infused. Unfortunately, when Burt used 3-mercaptopicolinate to inhibit gluconeogenesis and thereby induce hypoglycemia in fasted tumor-bearing subjects, infused glycerol served as gluconeogenic substrate, raising the serum glucose level. Agents which inhibit gluconeogenesis more distally - namely at the level of glucose-6-phosphatase or of fructosediphosphatase - may prevent the gluconeogenic response to glycerol, making glycerol-rescued hypoglycemic therapy of cancer feasible. In fact, certain new drugs being developed for diabetes therapy - chlorogenic acid derivatives and 'compound A' - are potent inhibitors of glucose-6-phosphatase, and both AICA riboside and 2,5-anhydro-D-mannitol have potential as clinical inhibitors of fructosediphosphatase. Insulin also can inhibit gluconeogenesis, both proximally and distally, and can potentiate hypoglycemia by promoting muscle glucose uptake; thus, coinfusion of high-dose insulin and of glycerol may represent an alternative viable strategy. Further research along these lines may enable glycerol-rescued hypoglycemia to become a feasible cancer therapy that has particular value as a complement to antiangiogenic measures.