RT Journal Article
SR Electronic
T1 2-Cyano-3,12-dioxooleana-1,9(11)-diene-28-oic Acid Disrupts Microtubule Polymerization: A Possible Mechanism Contributing to Apoptosis
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1158
OP 1165
DO 10.1124/mol.105.018572
VO 69
IS 4
A1 Robin D. Couch
A1 Neil J. Ganem
A1 Ming Zhou
A1 Veljko M. Popov
A1 Tadashi Honda
A1 Timothy D. Veenstra
A1 Michael B. Sporn
A1 Amy C. Anderson
YR 2006
UL http://molpharm.aspetjournals.org/content/69/4/1158.abstract
AB 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 β-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.