COX-2 inhibitors block chemotherapeutic agent-induced apoptosis prior to commitment in hematopoietic cancer cells.

Abstract

Enzymatic inhibitors of pro-inflammatory cyclooxygenase-2 (COX-2) possess multiple anti-cancer effects, including chemosensitization. These effects are not always linked to the inhibition of the COX-2 enzyme. Here we analyze the effects of three COX-2 enzyme inhibitors (nimesulide, NS-398 and celecoxib) on apoptosis in different hematopoietic cancer models. Surprisingly, COX-2 inhibitors strongly prevent apoptosis induced by a panel of chemotherapeutic agents. We selected U937 cells as a model of sensitive cells for further studies. Here, we provide evidence that the protective effect is COX-independent. No suppression of the low basal prostaglandin (PG)E(2) production may be observed upon treatment by COX-2 inhibitors. Besides, the non-active celecoxib analog 2,5-dimethyl-celecoxib is able to protect from apoptosis as well. We demonstrate early prevention of the stress-induced apoptotic signaling, prior to Bax/Bak activation. This preventive effect fits with an impairment of the ability of chemotherapeutic agents to trigger apoptogenic stress. Accordingly, etoposide-induced DNA damage is strongly attenuated in the presence of COX-2 inhibitors. In contrast, COX-2 inhibitors do not exert any anti-apoptotic activity when cells are challenged with physiological stimuli (anti-Fas, TNFα or Trail) or with hydrogen peroxide, which do not require internalization and/or are not targeted by chemoresistance proteins. Altogether, our findings show a differential off-target anti-apoptotic effect of COX-2 inhibitors on intrinsic vs. extrinsic apoptosis at the very early steps of intracellular signaling, prior to commitment. The results imply that an exacerbation of the chemoresistance phenomena may be implicated.

• Authors: Claudia Cerella, Cyril Sobolewski, Sébastien Chateauvieux, Estelle Henry, Michael Schnekenburger, Jenny Ghelfi, Mario Dicato, Marc Diederich
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 82 Issue 10 Pg. 1277-90 (Nov 15 2011) ISSN: 1873-2968 [Electronic] England
• PMID: 21745461 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cyclooxygenase 2 Inhibitors
• Nitrobenzenes
• Pyrazoles
• Sulfonamides
• N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
• Celecoxib
• nimesulide

Topics

• Antineoplastic Agents (adverse effects)
• Apoptosis (drug effects)
• Celecoxib
• Cell Line, Tumor
• Cyclooxygenase 2 Inhibitors (pharmacology)
• DNA Damage (drug effects)
• Dose-Response Relationship, Drug
• Hematologic Neoplasms (drug therapy, pathology)
• Humans
• K562 Cells
• Nitrobenzenes (pharmacology)
• Pyrazoles (pharmacology)
• Signal Transduction (drug effects)
• Stress, Physiological (drug effects)
• Sulfonamides (pharmacology)
• U937 Cells