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2-cyano-3,12-dioxooleana-1,9(11)-diene-28-oic acid disrupts microtubule polymerization: A possible mechanism contributing to apoptosis

  1. Author:
    Couch, R. D.
    Ganem, N. J.
    Zhou, M.
    Popov, V. M.
    Honda, T.
    Veenstra, T. D.
    Sporn, M. B.
    Anderson, A. C.

  2. Author Address

    Dartmouth Coll, Dept Chem, Hanover, NH 03755 USA. Dartmouth Coll Sch Med, Dept Biochem, Hanover, NH USA. Dartmouth Coll Sch Med, Dept Pharmacol & Toxicol, Hanover, NH USA. NCI, SAIC Federick Inc, Lab Proteom & Analyt Technol, Frederick, MD 21701 USA.;Anderson, AC, Univ Connecticut, Sch Pharm, Dept Med Chem, 69 N Eagleville Rd, Storrs, CT 06269 USA.;amy.anderson@uconn.edu
    1. Year: 2006
    2. Date: Apr
  2. Journal: Molecular Pharmacology
    1. 69
    2. 4
    3. Pages: 1158-1165
  4. Type of Article: Article
  5. ISSN: 0026-895X
  1. Abstract:

    The semisynthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) has several biological activities, including the induction of apoptosis in many cancer cell lines. To identify potential protein targets, immobilized biotinylated CDDO was used to screen the proteome of a human lymphoma cell line (U937) sensitive to CDDO-induced apoptosis. Tubulin was identified as one of several putative targets of CDDO. CDDO was shown to selectively bind to tubulin, with a dissociation constant of similar to 7 mu M, and to disrupt microtubules both in vivo and in vitro. CDDO inhibits tubulin polymerization in vitro, possibly through interactions with a hydrophobic site on beta-tubulin. The CDDO-tubulin interaction may also involve a reversible 1,4-addition with a protein sulfhydryl group. Unlike other known spindle poisons, CDDO does not result in a temporal increase in the mitotic index. Rather, CDDO seems to initiate apoptosis early in M phase.

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External Sources

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  2. DOI: 10.1124/mol.105.018572
  3. View record in Web of Science®
  4. WOS: 000236162600010

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