Hypoglycemia with glycerol salvage: a role in anti-neoplastic therapy?

Most tumors are obligate glucose consumers and severe glucose depletion has anti-neoplastic effects. However, an alternate energy source is necessary to support the host. Since glycerol is utilized by all hypoglycemic sensitive normal tissues but not tumors, glycerol may be an ideal alternate energy source. The effects of glycerol on tumor growth, animal survival during systemic hypoglycemia induced by 3-mercaptopicolinic acid (3-MP, a gluconeogenesis inhibitor), and effects of 3-MP on gluconeogenesis from glycerol were studied. Experiment 1-glycerol effect on tumor cell growth; and glycerokinase activity assay. Methylcholanthrene-induced (MCA) sarcoma cells were plated in either glucose free, glucose or glycerol containing medium. Cell counts and viabilities were recorded daily. Cells in glucose group had normal growth pattern and cell viability, while cell counts and viabilities in control and glycerol groups decreased markedly. F344 rats were injected with MCA-sarcoma cells in the flank. Glycerokinase activities in tumor and host liver were assayed on day 20. Activities were 12.3 +/- 2.8, 148.2 + 17.5 assayed on day 20. Activities were 12.3 +/- 2.8, 148.2 +/- 17.5 mumol/g protein/min in tumor and liver, respectively. Experiment 2-glycerol effect on animal survival during hypoglycemia induced by 3-MP. Following a 48 hour fast, 12 Fischer 344 rats were injected (ip) with 3-MP (200mg/kg) and randomized to saline or glycerol perfusion (100mg/kg/hr) groups. Four of 6 rats in the saline group died of hypoglycemia. All rats in the glycerol group survived, but blood glucose levels were increased as compared to the saline group. Experiment 3-3-MP effect on gluconeogenesis from glycerol as compared to lactate. 5 x 10(6) hepatocytes were incubated in glucose-free HBSS containing glycerol (20mM) or lactate (20mM) in the presence (0.5mM) or absence of 3-MP. Glucose production was assayed every 30 minutes for 2 hrs. Glucose production from glycerol was not significantly inhibited in the presence of 3-MP as compared to lactate.

Glycerol does not support MCA-sarcoma growth and promotes animal survival during severe systemic hypoglycemia induced by 3-MP. However, glycerol also led to increased gluconeogenesis in this model. The use of hypoglycemic agents with glycerol protection of host tissues warrants further study.