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

摘要: 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 COX-2 enzyme. Here we analyze three enzyme (nimesulide, NS-398 and celecoxib) on apoptosis in different hematopoietic cancer models. Surprisingly, strongly prevent induced by a panel chemotherapeutic agents. We selected U937 cells as model sensitive for further studies. Here, provide evidence that protective effect is COX-independent. No suppression low basal prostaglandin (PG)E(2) production may be observed upon treatment inhibitors. Besides, non-active celecoxib analog 2,5-dimethyl-celecoxib able protect from well. demonstrate early prevention stress-induced apoptotic signaling, prior Bax/Bak activation. This preventive fits with an impairment ability agents trigger apoptogenic stress. Accordingly, etoposide-induced DNA damage attenuated presence In contrast, do exert any anti-apoptotic activity when challenged physiological stimuli (anti-Fas, TNFα or Trail) hydrogen peroxide, which require internalization and/or targeted chemoresistance proteins. Altogether, our findings show differential off-target intrinsic vs. extrinsic at very steps intracellular commitment. The results imply exacerbation phenomena implicated.