Department of Pharmacology, SUNY Upstate Cancer Research Institute, State University of New York, 750 East Adams Street, Syracuse, NY 13210, USA.
Mol Cancer Res. 2013 Aug;11(8):856-64. doi: 10.1158/1541-7786.MCR-12-0177. Epub 2013 May 10.
We have developed a novel class (2-amino-4-phenyl-4H-chromene-3-carboxylate) of inhibitors of tubulin assembly by modifying HA14-1, which is a Bcl-2 inhibitor discovered by our group. Three of these compounds, mHA1, mHA6, and mHA11, showed in vitro cytotoxicities against tumor cells that were more potent and more stable than the backbone compound HA14-1, with nM IC50 values. In contrast, the cytotoxic effects of these compounds on normal cells were minimal. Computational docking, colchicine-tubulin competitive binding, and tubulin polymerization studies demonstrated that these compounds bind at the colchicine-binding site on tubulin and inhibit the formation of microtubules. Treatment of HL-60/Bcl-2 leukemia and CRL5908 lung cancer cells with these mHA compounds led to pronounced microtubule density decreases, G2/M cell cycle arrest, and apoptosis, as determined by immunofluorescence microscopy, flow cytometry, and DNA fragmentation analysis. Combined, these data identify a novel class of compounds that inhibit tubulin assembly and limit cancer cell phenotypes.
This study supports the continued development of novel anti-tubulin assembly inhibitors as potential anticancer agents.
我们通过对我们小组发现的 Bcl-2 抑制剂 HA14-1 进行修饰，开发了一类新型的微管组装抑制剂（2-氨基-4-苯基-4H-色烯-3-羧酸酯）。这三种化合物 mHA1、mHA6 和 mHA11 在体外对肿瘤细胞的细胞毒性比母核化合物 HA14-1 更强、更稳定，其 nM IC50 值更低。相比之下，这些化合物对正常细胞的细胞毒性很小。计算对接、秋水仙碱-微管蛋白竞争性结合和微管蛋白聚合研究表明，这些化合物结合在微管蛋白的秋水仙碱结合部位，并抑制微管的形成。通过免疫荧光显微镜、流式细胞术和 DNA 片段分析，用这些 mHA 化合物处理 HL-60/Bcl-2 白血病和 CRL5908 肺癌细胞后，微管密度明显下降，G2/M 细胞周期停滞，细胞凋亡。综合这些数据，确定了一类新型的抑制微管组装并限制癌细胞表型的化合物。
本研究支持继续开发新型的抗微管组装抑制剂作为潜在的抗癌药物。
