Roles of survivin isoforms in the chemopreventive actions of NSAIDS on colon cancer cells

Abstract

NSAIDs downregulate survivin (an apoptosis inhibitor), increase apoptosis and reduce growth of colon polyps and cancers. Recently, anti- and pro-apoptosis isoforms of survivin were identified. The roles of these isoforms in NSAID-induced colon cancer cell death have not been examined, and is the focus of this study. The anti-apoptosis isoforms, wild-type (WT) survivin and survivin-DeltaEx3, and the pro-apoptosis isoform, survivin-2b, were present in HT-29 and RKO cells. Indomethacin treatment significantly decreased WT survivin and survivin-DeltaEx3 (30.5+/-10.4% and 20.3+/-6.7%, respectively) but not survivin-2b mRNA in RKO cells. In HT-29 cells, all three isoform mRNAs were slightly decreased by indomethacin treatment. Consistently, indomethacin treatment dramatically reduced WT survivin protein in RKO but not HT-29 cells. Indomethacin treatment increased apoptosis and general cell death more significantly in RKO cells (75.7+/-1.1% cell death at 48 h) than in HT-29 cells (25.4+/-3.7% cell death at 48 h). Anti-sense suppression of survivin-2b mRNA increased resistance of both RKO and HT-29 cells to indomethacin. These data support a role for survivin isoforms in colon cancer cell apoptosis, and thus in prevention of colon cancer growth by NSAIDs.

Microspheres with pH modulated release: Design and characterization of formulation variables for colonic delivery

“…It reduces proliferation rates of HT-29 colon cancer cells (Kapitanović et al 2006). It also induces apoptosis by up-regulating pro-apoptotic genes and down-regulating anti-apoptotic genes and is therefore associated with potent inhibitory action on colon cancer growth (Mandayam et al 2007). However, the multiple dosing oral conventional formulation of indomethacin will result in systemic accumulation of the drug, leading to untoward side effects and adverse reactions (Marsh et al 1986).…”

Nutrient Availability Alters the Effect of Autophagy on Sulindac Sulfide-Induced Colon Cancer Cell Apoptosis

“…These results showed that inhibition of autophagy by 3-MA and Atg7 siRNA had significant effects on the half-life of the apoptosis inhibitor survivin under certain conditions. We previously determined that regulation of survivin levels by NSAIDs is a key factor for apoptosis induction in colon cancer cells [24]. survivin also regulates autophagy [25, 26].…”

Design and in vitro evaluation of formulations with pH and transit time controlled sigmoidal release profile for colon-specific delivery

“…It is reported to cause growth inhibition, induction of apoptosis, and reduction in proliferation rates of HT-29 colon cancer cells (5). It has been established recently that indomethacin down-regulates survivin (an apoptosis inhibitor) in the case of colon cancer, thereby causing apoptosis and cancer cell death (6). Indomethacin is also reported to decrease EP2 prostanoid receptor expression in colon cancer cells (7).…”