DOLASTATIN-15, A POTENT ANTIMITOTIC DEPSIPEPTIDE DERIVED FROM DOLABELLA-AURICULARIA - INTERACTION WITH TUBULIN AND EFFECTS ON CELLULAR MICROTUBULES
DOLASTATIN-15, A POTENT ANTIMITOTIC DEPSIPEPTIDE DERIVED FROM DOLABELLA-AURICULARIA - INTERACTION WITH TUBULIN AND EFFECTS ON CELLULAR MICROTUBULES
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DOI：
10.1016/0006-2952(92)90153-a
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发表时间：
1992-06-23
影响因子：
5.8
通讯作者：
HAMEL, E
中科院分区：
文献类型：
--
作者：
BAI, R;FRIEDMAN, SJ;HAMEL, E
Dolastatin 15是一种来源于耳廓多巴贝氏菌的7亚基脱肽，是一种有效的抗有丝分裂药物，其结构与抗微管蛋白制剂Dolastatin 10相似，Dolastatin 10是从同一生物中获得的一种5亚单位多肽。我们比较了Dolastatin 15和Dolastatin 10对培养细胞和微管蛋白生化性质的影响。Dolastatin 15与L1210小鼠白血病细胞、人Burkitt淋巴瘤细胞和中国仓鼠卵巢(CHO)细胞(分别与3、3和5 nM细胞株)的生长IC50值。对于Dolastatin 10，L1210和CHO细胞的IC50值分别为0.4和0.5 nM。在毒性浓度下，多司他丁15导致白血病和淋巴瘤细胞在有丝分裂中停滞。在CHO细胞中，Dolastatin 15和Dolastatin 10均导致IC50值的微管中度丧失，浓度高10倍时微管完全消失。尽管它的效力和处理细胞中微管的丢失，但在体外，Dolastatin 15与微管蛋白的相互作用很弱。其抑制谷氨酸诱导的微管蛋白聚合的IC50值为23mU-M，而Dolastatin 10和长春花碱的IC50值分别为1.2mU-M和1.5mU-M。Dolastatin 10非竞争性地抑制长春新碱与微管蛋白的结合，抑制核苷酸交换，稳定微管蛋白的秋水仙碱结合活性，并抑制微管蛋白依赖的GTP水解(Bai等人，Biochem Pharmacol 39：1941-1949,1990；Bai等人)。生物化学265：17141-17149,1990年)。然而，它的结构相似性表明，它可能弱结合在微管蛋白的“Vinca结构域”(我们假设的蛋白质的一个区域，物理上与长春花碱和美丹素类化合物的特定结合位置不同)，推测与Dolastatin 10在同一位置(“肽位置”)。
Dolastatin 15, a seven-subunit depsipeptide derived from Dolabella auricularia, is a potent antimitotic agent structurally related to the antitubulin agent dolastatin 10, a five-subunit peptide obtained from the same organism. We have compared dolastatin 15 with dolastatin 10 for its effects on cells grown in culture and on biochemical properties of tubulin. The IC50 values for cell growth were obtained for dolastatin 15 with L1210 murine leukemia cells, human Burkitt lymphoma cells, and Chinese hamster ovary (CHO) cells (3,3, and 5 nM with the three cell lines, respectively). For dolastatin 10, IC50 values of 0.4 and 0.5 nM were obtained with the L1210 and CHO cells, respectively. At toxic concentrations dolastatin 15 caused the leukemia and lymphoma cells to arrest in mitosis. In the CHO cells both dolastatin 15 and dolastatin 10 caused moderate loss of microtubules at the IC50 values and complete disappearance of microtubules at concentrations 10-fold higher. Despite its potency and the loss of microtubules in treated cells, the interaction of dolastatin 15 with tubulin in vitro was weak. Its IC50 value for inhibition of glutamate-induced polymerization of tubulin was 23-mu-M, as compared to values of 1.2-mu-M for dolastatin 10 and 1.5-mu-M for vinblastine. Dolastatin 10 noncompetitively inhibits the binding of vincristine to tubulin, inhibits nucleotide exchange, stabilizes the colchicine binding activity of tubulin, and inhibits tubulin-dependent GTP hydrolysis (Bai et al., Biochem Pharmacol 39: 1941-1949, 1990; Bai et al. J Biol Chem 265: 17141-17149, 1990). Only the latter reaction was inhibited by dolastatin 15. Nevertheless, its structural similarity to dolastatin 10 indicates that dolastatin 15 may bind weakly in the "vinca domain" of tubulin (a region of the protein we postulate to be physically close to but not identical with the specific binding site of vinca alkaloids and maytansinoids), presumably in the same site as dolastatin 10 (the "peptide site").