In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 8 ( 2013-08-01), p. 1381-1392
Abstract:
Proteasome inhibitors have been suggested as potential anticancer agents in many clinical trials. Recent evidence indicates that proteasomal deubiquitinase (DUB) inhibitors, bearing a different mechanism from that of traditional proteasome inhibitors, would be appropriate candidates for new anticancer drug development. In the present study, we describe the deubiquitinase inhibition of 19S regulatory particles (19S RP) by AC17, a 4-arylidene curcumin analog synthesized in our laboratory. Although 4-arylidene curcumin analogs were reported to act as inhibitory κB (IκB) kinase (IKK) inhibitors, AC17 instead induced a rapid and marked accumulation of ubiquitinated proteins without inhibiting proteasome proteolytic activities. In contrast to its parent compound, curcumin, which is a proteasome proteolytic inhibitor, AC17 serves as an irreversible deubiquitinase inhibitor of 19S RP, resulting in inhibition of NF-κB pathway and reactivation of proapoptotic protein p53. In addition, in a murine xenograft model of human lung cancer A549, treatment with AC17 suppresses tumor growth in a manner associated with proteasome inhibition, NF-κB blockage, and p53 reactivation. These results suggest that 4-arylidene curcumin analogs are novel 19S deubiquitinase inhibitors with great potential for anticancer drug development. Mol Cancer Ther; 12(8); 1381–92. ©2013 AACR.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.MCT-12-1057
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2062135-8
SSG:
12
