Pharmaceutical Sciences Faculty Publications

Title

2-Cyano-3,12-Dioxooleana-1,9(11)-Diene-28-Oic Acid Disrupts Microtubule Polymerization: A Possible Mechanism Contributing to Apoptosis

Document Type

Article

Publication Date

4-1-2006

Journal Title

Molecular Pharmacology

ISSN

0026-895X

Volume

69

Issue

4

First Page

1158

Last Page

1165

DOI

10.1124/mol.105.018572

PubMed ID

16407469

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 approximately 7 microM, 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.

Keywords

Binding sites, biopolymers, microscopy, fluorescence, microtubules, mitosis, oleanolic acid, tubulin

Share

COinS