Abstract
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.
Footnotes
-
This work was supported by funding from the National Institutes of Health (to H.C.J.) and from the Department of Science and Technology, Government of India (to D.P.).
- Abbreviations:
- 5-Br-nosc
- 5-bromonoscapine
- Rd 5-Br-nosc
- reduced 5-bromonoscapine
- FBS
- fetal bovine serum
- PIPES
- piperazine-N,N′-bis(2-ethanesulfonic acid)
- PBS
- phosphate-buffered saline
- PI
- propidium iodide
- DMSO
- dimethyl sulfoxide
- FITC
- fluorescein isothiocyanate
- Received October 11, 2002.
- Accepted December 16, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
