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.