Reduction of the growth rate of the Walker 256 tumor in rats by rhodamine 6G together with hypoglycemia

Previous attempts to use tumor energy metabolism as a target for antineoplastic therapy have used single agents aimed at inhibiting either glycolysis or oxidative phosphorylation. Since most tumor cells use both pathways for energy production, this approach is unlikely to succeed. The aim of this study was to simultaneously manipulate both sources of intracellular ATP to achieve more selective control of tumor growth. Rhodamine 6G (R6G) is a fluorochrome mitochondrial dye which inhibits oxidative phosphorylation. 3-Mercaptopicolinic acid inhibits gluconeogenesis and is a potent hypoglycemic agent in the fasting state. Dose-response relationships were established for R6G and 3-mercaptopicolinic acid, and a nontoxic dose of the compounds was selected for subsequent experiments. Thereafter, groups of rats (n = 7 per group) underwent s.c. implantation of Walker 256 carcinosarcoma. Following a 24-h fast each group received either saline, R6G (0.8 mg/kg), 3-mercaptopicolinic acid (40 mg/kg), or the combination given i.p. Seven days after tumor implantation animals were sacrificed, and tumors were exercised and weighed. Administration of R6G during a period of hypoglycemia significantly reduced the tumor growth rate when compared to control experiments (3.6 +/- 0.3 g cf. 7.1 +/- 0.7 g, mean +/- SE; P less than 0.05). In contrast, neither R6G nor the period of hypoglycemia alone significantly affected tumor growth. These results suggest that simultaneous manipulation of oxidative phosphorylation and glycolysis may be used to selectively inhibit tumor growth in vivo.