Activation of the p38- pathway by a novel monoketone curcumin analog, EF24, suggests a potential combination strategy

• Type of Material: Article
• Authors: Shala L. Thomas, Emory University; Jing Zhao, Emory University; Zijian Li, Emory University; Bin Lou, Emory University; Yuhong Du, Emory University; Jamie Purcell, Emory University; James P Snyder, Emory University; Fadlo Khuri, Emory University; Dennis C Liotta, Emory University; Haian Fu, Emory University
• Language: English
• Date: 2010-11-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bcp.2010.06.048
• Title of Journal or Parent Work: Biochemical Pharmacology
• ISSN: 0006-2952
• Volume: 80
• Issue: 9
• Start Page: 1309
• End Page: 1316
• Grant/Funding Information: This work was supported in part by grants from the National Institutes of Health (P01 CA116676 and SPORE P50 CA128613 to FRK and HF) and a fellowship from the American Association for the Advancement of Science/Packard Foundation (SLT).
• Keywords: lung cancer; EF24; p38; p38 inhibitors; curcumin analogs
• Research Categories: Chemistry, Biochemistry; Health Sciences, Pharmacology; Health Sciences, Oncology

Abstract

Increasing attention has been given to the anti-cancer effects of curcumin and the ability of this natural product to inhibit cancer cell proliferation. New curcumin analogs have been developed to optimize the in vitro and in vivo activity of the parent compound yet retain the same safety profile. EF24, a fluorinated synthetic analog, surpasses curcumin in its ability to inhibit cancer cell viability and down-regulate TNFα-induced NF-κB activation. Here we report a critical role of the p38-mediated signaling pathway in the determination of lung cancer cell’s sensitivity to EF24. We have found that EF24-induced decease of lung cancer cell viability was accompanied by upregulated mitogen-activated protein kinases (MAPK) as evidenced by increased phosphorylation of ERK1/2, JNK, and p38. Pharmacological investigation led to our suggestion that EF24 triggers a negative feedback loop through p38 activation. In support of this model, inhibition of p38, either by small molecule inhibitors or through an RNAi-mediated knockdown approach, enhanced the EF24 induced apoptotic death of A549 cells. Thus, inhibition of p38 may boost the EF24 anticancer effect. Indeed, a combination of EF24 and SB203580, a p38 inhibitor, synergistically inhibited clonogenic activity of A549 lung cancer cells and induced their apoptosis as reflected by poly(ADP-ribose) polymerase cleavage, the accumulation of the sub-G1 fraction of cells, and apoptotic cell staining. These studies offer a novel strategy that combines the curcumin analog EF24 with a p38 inhibitor for potentially enhanced therapy in the treatment of lung cancer.