Zhou Jun, Gupta Kamlesh, Aggarwal Shefali, Aneja Ritu, Chandra Ramesh, Panda Dulal, Joshi Harish C
Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia 30322, USA.
Mol Pharmacol. 2003 Apr;63(4):799-807. doi: 10.1124/mol.63.4.799.
Noscapine, a microtubule-interfering agent, has been shown to arrest mitosis, to induce apoptosis, and to have potent antitumor activity. We report herein that two brominated derivatives of noscapine, 5-bromonoscapine (5-Br-nosc) and reduced 5-bromonoscapine (Rd 5-Br-nosc), have higher tubulin binding activity than noscapine and affect tubulin polymerization differently from noscapine. In addition, they are able to arrest cell cycle progression at mitosis at concentrations much lower than noscapine. Interestingly, whereas noscapine-arrested cells have nearly normal bipolar spindles, cells arrested by 5-Br-nosc and Rd 5-Br-nosc form multipolar spindles. Nevertheless, noscapine and the two derivatives all affect the attachment of chromosomes to spindle microtubules and they impair the tension across paired kinetochores to similar degrees. 5-Br-nosc and Rd 5-Br-nosc are also more active than noscapine in inhibiting the proliferation of various human cancer cells, including those that are resistant to paclitaxel and epothilone. Our results thus indicate a great potential for the use of 5-Br-nosc and Rd 5-Br-nosc both as biological tools for studying microtubule-mediated processes and as chemotherapeutic agents for the treatment of human cancers.
那可丁是一种微管干扰剂，已被证明可阻止有丝分裂、诱导细胞凋亡并具有强大的抗肿瘤活性。我们在此报告，那可丁的两种溴化衍生物，5-溴那可丁（5-Br-nosc）和还原型5-溴那可丁（Rd 5-Br-nosc），比那可丁具有更高的微管蛋白结合活性，并且对微管蛋白聚合的影响与那可丁不同。此外，它们能够在比那可丁低得多的浓度下使细胞周期进程在有丝分裂期停滞。有趣的是，虽然那可丁停滞的细胞具有几乎正常的双极纺锤体，但被5-Br-nosc和Rd 5-Br-nosc停滞的细胞形成多极纺锤体。然而，那可丁和这两种衍生物均会影响染色体与纺锤体微管的附着，并且它们对成对动粒间张力的损害程度相似。5-Br-nosc和Rd 5-Br-nosc在抑制各种人类癌细胞（包括对紫杉醇和埃坡霉素耐药的癌细胞）的增殖方面也比那可丁更具活性。因此，我们的结果表明，5-Br-nosc和Rd 5-Br-nosc作为研究微管介导过程的生物学工具以及作为治疗人类癌症的化学治疗剂具有巨大潜力。
