Cox-2 is needed but not sufficient for apoptosis induced by Cox-2 selective inhibitors in colon cancer cells

Abstract

The role of Cox-2 in NSAID-induced apoptosis is debated. We studied the role of Cox-2 inhibition in apoptosis induced by a selective Cox-2 inhibitor, SC236 (a structural analogue of celecoxib) in two colon cancer cell lines, HT29 (expressing Cox-2 protein) and HCT116 (not expressing Cox-2 protein). Apoptosis was quantified by flow cytometry. SC236 0-75 microM decreased cell numbers and induced apoptosis to identical levels in HT29 and HCT116 cells. However, SC236, concentrations >75 microM reduced Cox-2 protein expression in HT29 cells and induced greater levels of apoptosis in HT29 than in HCT116 cells. In contrast, sulindac sulfide (SSD) (which inhibits Cox-1 and Cox-2) 0-200 microM or sulindac sulfone (SSN) 0-500 microM (without significant activity against Cox-1 or Cox-2) caused identical decreases in cell number and increases in apoptosis in HT29 and HCT116 cells. Neither SSD nor SSN altered the expression of Cox-2 in HT29 cells. To determine that the higher levels of apoptosis in HT29 cells with SC236 >75 microM were related to decreased Cox-2 protein levels, we decreased Cox-2 protein expression in HT29 cells with curcumin (diferuloylmethane) and studied its effect on SC236-induced apoptosis. Curcumin augmented apoptosis induced by SC236 in HT29 cells but not in Cox-2 lacking HCT116 cells. In conclusion, selective Cox-2 inhibitors can induce apoptosis independent of Cox-2 expression. However they may selectively target cells that express Cox-2 by decreasing their Cox-2 protein expression.

Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer

“…Therefore, Celecoxib is not simply blocking the effect of COX-2, but is also perturbing COX-2 protein production; a finding noted in previous studies (Cheng et al, 2002;Agarwal et al, 2003). In COX-2 expressing HT29 colon cancer cell lines, COX-2 inhibition with another selective COX-2 inhibitor SC236 (a structural analogue of Celecoxib) showed that at high levels of inhibitor (concentrations greater than 75 mm), COX-2 enzyme activity was completely inactivated.…”

“…Whereas Sulindac sulphide (an inhibitor of COX-1 and COX-2) did not promote any changes in apoptosis and also showed no decrease in COX-2 protein expression) (Agarwal et al, 2003). The antiapoptotic effects of COX-2 were better correlated to decreases in COX-2 protein expression than inhibition of enzymatic activity (Agarwal et al, 2003). It has been suggested that the prostaglandin products of COX-2, mainly PgE2, positively feed back to produce enhanced COX-2 protein expression (Faour et al, 2001).…”

“…Decreased levels of COX-2 protein expression and increases in apoptosis were seen. Whereas Sulindac sulphide (an inhibitor of COX-1 and COX-2) did not promote any changes in apoptosis and also showed no decrease in COX-2 protein expression) (Agarwal et al, 2003). The antiapoptotic effects of COX-2 were better correlated to decreases in COX-2 protein expression than inhibition of enzymatic activity (Agarwal et al, 2003).…”

Preadministration of High-Dose Salicylates, Suppressors of NF-κB Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy

“…165 There are a number of reports that cox-2 activity is associated with a suppression of spontaneous apoptosis in various types of cancer cells; conversely, cox-2 inhibitors have been reported to boost the responsiveness of certain cancer cell lines to cytotoxic drugs or radiotherapy. [166][167][168][169][170][171][172][173][174][175][176][177][178][179][180][181][182][183][184] (Some of these results need to be viewed circumspectly, however, as some cox-2-specific inhibitors such as celecoxib can exert proapoptotic effects that are independent of cox-2 inhibition. 185 ) Although the impact of cox-2 on apoptosis is likely mediated by PGE2 or other prostanoids, the mechanisms involved are less well understood than those that mediate the impact of NF-κB; increased expression of Bad and/or decreased expression of Bcl-2 appear to play a role in some cell lines.…”

Entrapment of curcumin into monoolein-based liquid crystalline nanoparticle dispersion for enhancement of stability and anticancer activity

“…[2][3][4][5] Specifically, curcumin-induced apoptosis in human breast tumor cell lines (MCF-7 and MDAMB), and in a human hepatocellular carcinoma cell line (HepG2), in a dose-dependent and time-dependent manner. 6 Curcumin has also been shown to possess apoptotic activity against human colon cancer cells, 7 stomach and skin tumors, 8 and prostate cancer cells.…”