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Vol. 63, Issue 4, 799-807, April 2003

Brominated Derivatives of Noscapine Are Potent Microtubule-interfering Agents That Perturb Mitosis and Inhibit Cell Proliferation

Jun Zhou, Kamlesh Gupta, Shefali Aggarwal, Ritu Aneja, Ramesh Chandra, Dulal Panda, and Harish C. Joshi

Graduate Program in Biochemistry, Cell and Developmental Biology (J.Z.) and Department of Cell Biology (J.Z., H.C.J.), Emory University, Atlanta, Georgia; Bhupat and Jyoti Mehta School of Biosciences and Bioengineering, Indian Institute of Technology, Bombay, Mumbai, India (K.G., D.P.); Dr. B. R. Ambedkar Center for Biomedical Research (S.A., R.C.) and Department of Chemistry (R.A.), University of Delhi, Delhi, India

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.

Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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