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Original Article

2-Cyano-3,12-dioxooleana-1,9(11)-diene-28-oic Acid Disrupts Microtubule Polymerization: A Possible Mechanism Contributing to Apoptosis

Department of Chemistry, Dartmouth College, Hanover, New Hampshire (R.D.C., V.M.P., T.H., A.C.A.); Departments of Biochemistry (N.J.G.) and Pharmacology and Toxicology (M.B.S.), Dartmouth Medical School, Hanover, New Hampshire; and Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland (M.Z., T.D.V.)

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 7 µM, and to disrupt microtubules both in vivo and in vitro. CDDO inhibits tubulin polymerization in vitro, possibly through interactions with a hydrophobic site on -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.

Address correspondence to: Amy C. Anderson, Department of Medicinal Chemistry, School of Pharmacy, University of Connecticut, 69 North Eagleville Rd., Storrs, CT 06269-3092. E-mail: amy.anderson{at}uconn.edu

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