Inhibition of melanoma tumor growth by a novel inhibitor of glucosylceramide synthase

Tumor ganglioside metabolism has been implicated in modulating tumor formation and progression. We found previously that transient ganglioside depletion by inhibition of glucosylceramide synthesis of MEB4 melanoma cells in vitro reduced their tumorigenic capability. Here, we have established that treatment of the host with a novel p.o. inhibitor of glucosylceramide synthesis, the imino sugar OGT2378, inhibits MEB4 melanoma tumor growth in a syngeneic, orthotopic murine model. The glucosylceramide and ganglioside content of MEB4 cells exposed to 20 micro M OGT2378 in culture were reduced by 93 and >95%, respectively, without either cytotoxic or antiproliferative effects. Administered in the diet to C57BL/6 mice, 2500 mg/kg/day OGT2378 was well tolerated in vivo and biologically active, depleting host tissue (hepatic) gangliosides by 82% and tumor gangliosides by >98%. p.o. treatment with OGT2378 starting 3 days before intradermal tumor inoculation of 4 x 10(4) MEB4 cells, and continuing for 4 weeks, resulted in a 10-fold lower mean tumor volume at the end of treatment (60 versus 538 mm(3), P < 0.0001). Even when OGT2378 treatment was initiated 7 days after tumor inoculation, tumor growth was similarly impeded (61 versus 620 mm(3), P < 0.0001), demonstrating an effect on an established tumor. The effectiveness of p.o. OGT2378 in this murine model suggests that inhibition of glycosphingolipid synthesis is a promising and now feasible novel therapeutic approach to inhibit tumor progression.