2-cyano-3,12-dioxooleana-1,9(11)-diene-28-oic acid disrupts microtubule polymerization: a possible mechanism contributing to apoptosis.
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.
Couch
Robin D
RD
Department of Medicinal Chemistry, School of Pharmacy, University of Connecticut, 69 North Eagleville Rd., Storrs, CT 06269-3092, USA.
Ganem
Neil J
NJ
Zhou
Ming
M
Popov
Veljko M
VM
Honda
Tadashi
T
Veenstra
Timothy D
TD
Sporn
Michael B
MB
Anderson
Amy C
AC
D001665:Binding Sites; D001704:Biopolymers; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008938:Mitosis; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D001704:Biopolymers; D014404:Tubulin; D009828:Oleanolic Acid