title: Activation of the p38 pathway by a novel monoketone curcumin analog, EF24, suggests a potential combination strategy.
abstract: Increasing attention has been given to the anticancer 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-G(1) 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.
authors.affiliation: Emory University, Atlanta, GA 30322, USA.
authors.forename: Shala L
authors.initials: SL
authors.lastname: Thomas
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Zijian
authors.initials: Z
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Lou
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.forename: Jamie
authors.initials: J
authors.lastname: Purcell
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Dennis
authors.initials: D
authors.lastname: Liotta
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001597:Benzylidene Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010881:Piperidones / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: C524042:3,5-bis(2-fluorobenzylidene)piperidin-4-one; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D007093:Imidazoles; D010881:Piperidones; D011725:Pyridines; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580