Pioglitazone inhibits growth of carcinoid cells and promotes TRAIL-inducedapoptosis by induction of p21(waf1/cip1)

Background/Aims: We investigated the effect of the peroxisome proliferator- activated receptor-gamma (PPAR-gamma) agonist pioglitazone on growth and TR AIL-induced apoptosis in carcinoid cells. Methods: Carcinoid cells were inc ubated without and with pioglitazone. Effects on growth were examined by ce ll count and cell cycle analysis. p21(waf1/cip1) expression was determined by Western blotting. Cytotoxicity assay was performed by FACS analysis. Res ults: Pioglitazone suppressed the growth and induced apoptosis of carcinoid cells. Additionally, pioglitazone significantly enhanced carcinoid cell de ath induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligan d (TRAIL). The enhancement of TRAIL-induced apoptosis was associated with a n upregulation of cyclin-dependent kinase inhibitor p21(waf1/cip1) in piogl itazone-treated carcinoid cells. Importantly, overexpression of p21(waf1/ci p1) in carcinoid cells by adenoviral gene transfer of p21 sensitized them t o TRAIL-induced apoptosis. Conclusions: These results suggest that pioglita zone inhibits cell growth and sensitizes cells to TRAIL-induced apoptosis b y induction of p21(waf1/cip1). Therefore, pioglitazone can be an effective therapeutic adjuvant for the treatment of carcinoid tumors. Copyright (C) 2 001 S. Karger AG, Basel.