Small Molecule Therapeutics Deubiquitinase Inhibition of 19S Regulatory Particles by 4-Arylidene Curcumin Analog AC17 Causes NF-kB Inhibition and p53 Reactivation in Human Lung Cancer Cells

Proteasome inhibitors have been suggested as potential anticancer agents in many clinical trials. Recent evidence indicates that proteasomal deubiquitinase (DUB) inhibitors, bearing a differentmechanism 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 kB (IkB) 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-kB 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-kB 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.