Spongistatin 1, a highly cytotoxic, sponge-derived, marine natural product that inhibits mitosis, microtubule assembly, and the binding of vinblastine to rubulin

A highly cytotoxic macrocyclic lactone polyether has been isolated from a Spongia species and named spongistatin 1. With L1210 murine leukemia cells an IC₅₀ value for cell proliferation of 20 pM was obtained, and an increase in the mitotic index concordant with the decrease in cell number was observed. Kangaroo rat kidney PtK1 cells were examined by indirect immunofluorescence with a spongistatin 1 concentration that caused 50% reduction in cellular protein (0.3 nM) and with a 10-fold higher concentration. These cells displayed mitotic and nuclear aberrations at both concentrations, and intracellular microtubules were reduced in number at the lower concentration and disappeared at the higher. Similar changes in PtK1 cells were observed after treatment with equivalent toxic concentrations of the antimitotic agents colchicine, vinblastine, halichondrin B, and dolastatin 10. Spongistatin 1 inhibited the glutamate-induced polymerization of purified tubulin (IC₅₀ value of 3.6 μM versus 2.1 μM for dolastatin 10 and vinblastine and 5.2 μM for halichondrin B). Spongistatin 1 had no effect on the binding of colchicine to tubulin, but it was a potent inhibitor of the binding of vinblastine and GTP to tubulin. In initial experiments with 5 μM tubulin and 5 μM vinblastine, spongistatin 1 and dolastatin 10 both had IC₅₀ values of 2 μM, whereas halichondrin B had an IC₅₀ value of 5 μM. Spongistatin 1 thus represents a new member of the group of complex natural products that inhibit mitosis by binding in the Vinca alkaloid domain of tubulin.