Bai R, Cichacz Z A, Herald C L, Pettit G R, Hamel E
Laboratory of Molecular Pharmacology, National Cancer Institute, Institutes of Health, Bethesda, Maryland 20892.
Mol Pharmacol. 1993 Oct;44(4):757-66.
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 microM versus 2.1 microM for dolastatin 10 and vinblastine and 5.2 microM 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 microM tubulin and 5 microM vinblastine, spongistatin 1 and dolastatin 10 both had IC50 values of 2 microM, whereas halichondrin B had an IC50 value of 5 microM. 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.
从一种海绵属物种中分离出了一种具有高度细胞毒性的大环内酯聚醚，并将其命名为海绵抑素1。对于L1210小鼠白血病细胞，获得了细胞增殖的IC50值为20 pM，并且观察到有丝分裂指数的增加与细胞数量的减少相一致。用导致细胞蛋白减少50%的海绵抑素1浓度（0.3 nM）以及10倍高的浓度，通过间接免疫荧光法检测了袋鼠肾PtK1细胞。在这两种浓度下，这些细胞均表现出有丝分裂和核异常，并且在较低浓度下细胞内微管数量减少，在较高浓度下微管消失。在用等效毒性浓度的抗有丝分裂剂秋水仙碱、长春碱、海兔毒素B和多拉司他汀10处理后，在PtK1细胞中观察到了类似的变化。海绵抑素1抑制了谷氨酸诱导的纯化微管蛋白的聚合（IC50值为3.6 microM，多拉司他汀10和长春碱为2.1 microM，海兔毒素B为5.2 microM）。海绵抑素1对秋水仙碱与微管蛋白的结合没有影响，但它是长春碱和GTP与微管蛋白结合的有效抑制剂。在使用5 microM微管蛋白和5 microM长春碱的初始实验中，海绵抑素1和多拉司他汀10的IC50值均为2 microM，而海兔毒素B的IC50值为5 microM。因此，海绵抑素1代表了一类复杂天然产物中的新成员，这类天然产物通过在微管蛋白的长春花生物碱结构域结合来抑制有丝分裂。
