N-（2，6-二甲氧基吡啶-3-取代）-9-甲基咔唑-3-磺酰胺（IG-105）作为全新小分子微管蛋白配体药物的抗肿瘤作用，特点及分子机制
摘要
N-(2,6-二甲氧基吡啶-3-取代)-9-甲基咔唑-3-磺酰胺(IG-105)是由我们实验室发现并合成的结构新颖,靶点明确,体内外抗肿瘤活性强,安全性高,具有自主知识产权的小分子微管解聚剂。IG-105在体外对8种类型10株人肿瘤细胞均具有较强的抗增殖活性,IC_(50)在0.01-0.30μmol/L之间。对临床常用抗肿瘤药物耐药的癌细胞,IG-105也显示了很强的生长抑制作用。IG-105不是P-glycoprotein的转运底物,是其抗耐药的原因之一。IG-105的第一靶点是微管蛋白,计算机分子模拟对接和生物学竞争性结合实验均证明IG-105能特异地结合在微管蛋白的秋水仙碱位点。体外微管动力学实验表明IG-105与秋水仙碱位点结合的结果是抑制微管蛋白组装,IC_(50)为3μmol/L;免疫荧光染色表明IG-105抑制细胞内微管蛋白的装配,破坏细胞内细胞骨架网络。细胞形态学和流式细胞检测结果表明,在细胞微管装配受到抑制后,IG-105可以选择性阻断肿瘤细胞于有丝分裂期(M期),并引起肿瘤细胞凋亡。IG-105作用于人肝癌细胞Bel-7402后,可以持续上调Cyclin B1水平,下调Cyclin D1水平,在生化水平证实了IG-105对细胞周期的阻断作用。IG-105可以剂量依赖性和时间依赖性的方式作用于Bel-7402细胞产生DNA梯带,诱导抗凋亡蛋白Bcl-2持续磷酸化灭活,上调p53水平并激活Caspase-3/8/9的活性,经线粒体途径诱导细胞死亡。22000个人基因芯片测定的结果提示IG-105可能对其它重要生命信号网络不产生明显影响。
在动物治疗实验中,裸鼠隔天腹腔注射100,175或275 mg/kg的IG-105,经4周治疗,人肝癌Bel-7402移植瘤在其体内生长抑制率分别为81%,87%和98%,对照药奥沙利铂和多柔比星抑瘤率分别为57%和60%。在联合化疗实验中,IG-105(175 mg/kg)联合奥沙利铂(5 mg/kg)对Bel-7402移植瘤体内生长抑制率为96%,IG-105(175 mg/kg)联合多柔比星(1 mg/kg)的抑瘤率为89%。100mg/kg和200 mg/kg的IG-105抑制人乳腺癌MCF-7移植瘤在裸鼠体内生长,抑瘤率分别为76%和93%。IG-105急性毒性低,半数致死量(LD_(50))大于1000mg/kg。急毒实验周期内,1000 mg/kg剂量组的小鼠行为正常,未出神经性毒性反应,体重无明显下降。肝脏,肾脏,心脏,脾脏,肺脏,脾脏的组织病理学均正常。IG-105的人血浆蛋白结合率高,为98%左右。
IG-105靶点明确,作用机制清楚,体内外抗肿瘤活性高,对耐药肿瘤有效,安全性好,治疗指数高,具有明显的临床应用前景。已申请中国专利(200510105255.5)和国际专利(PCT/CN2006/002298)各1项。本论文的部分工作发表在Clinical Cancer Research(2008,in press)。
We have synthesized a new tubulin ligand N-(2,6-dimethoxypyridine-3-yl)-9-methyl-carbazole-3-sulfonamide(IG-105) showing potent activity against a variety of human cancer cells with low IC_(50) values ranging from 0.01 to 0.3μmol/L.Interestingly,it was also very active in tumor cells that were resistant to the known tubulin-active anticancer drugs,such as paclitaxel and vincristine.Pgp ATPase activity assay showed that IG-105 was not a P-glycoprotein substrate.The primary action of IG-105 was to inhibit microtubule assembly from intracellular tubulin pool.In the cell free system,IG-105 inhibited tubulin polymerization with an ICs0 of 3μmol/L.In the live cell system,IG-105 caused wild microtubule de-polymerization and whole cytoskeleton network disruption.Using computational molecular docking as well as tubulin competition binding assay we identified colchicine pocket on tubulin as the IG-105's selective binding site.Further,IG-105 can induce M-phase arrest and following cell death characterized with the fragmented DNA in Bel-7402 cells.Accordingly,the up-regulated expression of Cyclin B1 as well as the down-regulation of Cyclin D1 by IG-105 was detected in the arrested cells. IG-105 induced programmed cell death via the mitochondrial pathways mediated through Bcl-2 phosphorylation,p53 up-regulation and Caspase-3/8/9 activity increase.DNA microarray analysis was performed on the IG-105-treated cells to learn the global change of the expression of 22,000 human genes,and suggested that IG-105 might be considerably specific for the tubutin-related cascade described above,rather than for other important life-determining pathways.
Animal studies showed that IG-105 monotherapy yielded 81%inhibition of tumor growth for Bel-7402 human hepatoma in nude mice at 100 mg/kg(i.p.,q2d),and completely inhibited the growth of Bel-7402 hepatoma at 275 mg/kg(i.p.,q2d).MCF-7 human breast cancer demonstrated a similar response to IG-105.In combination with oxaliplatin or doxorubicin,IG-105 converted each of these subcurative compounds into a curative treatment with a complete inhibition of tumor growth of Bel-7402 hepatoma.The combination was more efficient than either drug.In no experiment was toxicity increased by combination chemotherapy.IG-105 showed a good safety in mice even when the dose of IG-105 was over 1000 mg/kg(i.p.).No evidence of histopathological damage was found in liver,kidney,heart,lung and spleen.In addition,the human plasma protein binding rate of IG-105 was also investigated in the study.
In summary,IG-105(1) inhibits microtubule assembly by selectively binding at colchicine pocket,(2) shows a potent anticancer activity in the naive and drug-resistant tumors,and(3) completely inhibits human tumor growth in mice with good safety.We consider IG-105 merits further investigation.
在动物治疗实验中,裸鼠隔天腹腔注射100,175或275 mg/kg的IG-105,经4周治疗,人肝癌Bel-7402移植瘤在其体内生长抑制率分别为81%,87%和98%,对照药奥沙利铂和多柔比星抑瘤率分别为57%和60%。在联合化疗实验中,IG-105(175 mg/kg)联合奥沙利铂(5 mg/kg)对Bel-7402移植瘤体内生长抑制率为96%,IG-105(175 mg/kg)联合多柔比星(1 mg/kg)的抑瘤率为89%。100mg/kg和200 mg/kg的IG-105抑制人乳腺癌MCF-7移植瘤在裸鼠体内生长,抑瘤率分别为76%和93%。IG-105急性毒性低,半数致死量(LD_(50))大于1000mg/kg。急毒实验周期内,1000 mg/kg剂量组的小鼠行为正常,未出神经性毒性反应,体重无明显下降。肝脏,肾脏,心脏,脾脏,肺脏,脾脏的组织病理学均正常。IG-105的人血浆蛋白结合率高,为98%左右。
IG-105靶点明确,作用机制清楚,体内外抗肿瘤活性高,对耐药肿瘤有效,安全性好,治疗指数高,具有明显的临床应用前景。已申请中国专利(200510105255.5)和国际专利(PCT/CN2006/002298)各1项。本论文的部分工作发表在Clinical Cancer Research(2008,in press)。
We have synthesized a new tubulin ligand N-(2,6-dimethoxypyridine-3-yl)-9-methyl-carbazole-3-sulfonamide(IG-105) showing potent activity against a variety of human cancer cells with low IC_(50) values ranging from 0.01 to 0.3μmol/L.Interestingly,it was also very active in tumor cells that were resistant to the known tubulin-active anticancer drugs,such as paclitaxel and vincristine.Pgp ATPase activity assay showed that IG-105 was not a P-glycoprotein substrate.The primary action of IG-105 was to inhibit microtubule assembly from intracellular tubulin pool.In the cell free system,IG-105 inhibited tubulin polymerization with an ICs0 of 3μmol/L.In the live cell system,IG-105 caused wild microtubule de-polymerization and whole cytoskeleton network disruption.Using computational molecular docking as well as tubulin competition binding assay we identified colchicine pocket on tubulin as the IG-105's selective binding site.Further,IG-105 can induce M-phase arrest and following cell death characterized with the fragmented DNA in Bel-7402 cells.Accordingly,the up-regulated expression of Cyclin B1 as well as the down-regulation of Cyclin D1 by IG-105 was detected in the arrested cells. IG-105 induced programmed cell death via the mitochondrial pathways mediated through Bcl-2 phosphorylation,p53 up-regulation and Caspase-3/8/9 activity increase.DNA microarray analysis was performed on the IG-105-treated cells to learn the global change of the expression of 22,000 human genes,and suggested that IG-105 might be considerably specific for the tubutin-related cascade described above,rather than for other important life-determining pathways.
Animal studies showed that IG-105 monotherapy yielded 81%inhibition of tumor growth for Bel-7402 human hepatoma in nude mice at 100 mg/kg(i.p.,q2d),and completely inhibited the growth of Bel-7402 hepatoma at 275 mg/kg(i.p.,q2d).MCF-7 human breast cancer demonstrated a similar response to IG-105.In combination with oxaliplatin or doxorubicin,IG-105 converted each of these subcurative compounds into a curative treatment with a complete inhibition of tumor growth of Bel-7402 hepatoma.The combination was more efficient than either drug.In no experiment was toxicity increased by combination chemotherapy.IG-105 showed a good safety in mice even when the dose of IG-105 was over 1000 mg/kg(i.p.).No evidence of histopathological damage was found in liver,kidney,heart,lung and spleen.In addition,the human plasma protein binding rate of IG-105 was also investigated in the study.
In summary,IG-105(1) inhibits microtubule assembly by selectively binding at colchicine pocket,(2) shows a potent anticancer activity in the naive and drug-resistant tumors,and(3) completely inhibits human tumor growth in mice with good safety.We consider IG-105 merits further investigation.
引文
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