BACKGROUND/AIMS: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated and regulates cell growth and survival of various cancer cells. We investigated the anti-tumor effect of AG490, a Janus kinase 2 specific inhibitor, inhuman hepatoma cells. METHODS: Effects of AG490 on STAT3 activation, on cell-growth and survival, and on the expression of cell-cycle- and apoptosis-related proteins were evaluated in Huh-1, Huh-7, HepG2 and Hep3B cells. Next, whether AG490 renders hepatoma cells susceptible to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was examined in vitro and in vivo. RESULTS: Constitutively activated STAT3 through tyrosine phosphorylation was detected in all hepatoma cells. AG490 inhibited the phosphorylation of STAT3 and its activity. AG490 induced cell cycle arrest in Huh-1, Huh-7 and HepG2 through cyclin D1 downregulation, and induced marked apoptosis in Hep3B. AG490 downregulated at least one of the anti-apoptotic proteins, Bcl-xL, survivin or XIAP in all hepatoma cells. AG490 sensitized Huh-1, Huh-7 and HepG2 to TRAIL-induced apoptosis in vitro. Intraperitoneal injection of AG490, the combination of AG490 and TRAIL more greatly, repressed the growth of subcutaneous Huh-7 tumors in athymic mice. CONCLUSIONS: Abrogation of constitutive activation of STAT3 by AG490 enhances the anti-tumor activity of TRAIL against human hepatoma cells.
BACKGROUND/AIMS: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated and regulates cell growth and survival of various cancer cells. We investigated the anti-tumor effect of AG490, a Janus kinase 2 specific inhibitor, inhuman hepatoma cells. METHODS: Effects of AG490 on STAT3 activation, on cell-growth and survival, and on the expression of cell-cycle- and apoptosis-related proteins were evaluated in Huh-1, Huh-7, HepG2 and Hep3B cells. Next, whether AG490 renders hepatoma cells susceptible to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was examined in vitro and in vivo. RESULTS: Constitutively activated STAT3 through tyrosine phosphorylation was detected in all hepatoma cells. AG490 inhibited the phosphorylation of STAT3 and its activity. AG490 induced cell cycle arrest in Huh-1, Huh-7 and HepG2 through cyclin D1 downregulation, and induced marked apoptosis in Hep3B. AG490 downregulated at least one of the anti-apoptotic proteins, Bcl-xL, survivin or XIAP in all hepatoma cells. AG490 sensitized Huh-1, Huh-7 and HepG2 to TRAIL-induced apoptosis in vitro. Intraperitoneal injection of AG490, the combination of AG490 and TRAIL more greatly, repressed the growth of subcutaneous Huh-7tumors in athymic mice. CONCLUSIONS: Abrogation of constitutive activation of STAT3 by AG490 enhances the anti-tumor activity of TRAIL against humanhepatoma cells.
Authors: S Marozin; J Altomonte; K A Muñoz-Álvarez; A Rizzani; E N De Toni; W E Thasler; R M Schmid; O Ebert Journal: Cancer Gene Ther Date: 2015-05-01 Impact factor: 5.987
Authors: Vladimir N Ivanov; Shanaz A Ghandhi; Hongning Zhou; Sarah X Huang; Yunfei Chai; Sally A Amundson; Tom K Hei Journal: Exp Cell Res Date: 2011-04-02 Impact factor: 3.905
Authors: Curtis J Henrich; Cheryl L Thomas; Alan D Brooks; Nancy Lynn Booth; Evan M Lowery; Richard J Pompei; James B McMahon; Thomas J Sayers Journal: Apoptosis Date: 2012-01 Impact factor: 4.677
Authors: T Noda; H Nagano; I Takemasa; S Yoshioka; M Murakami; H Wada; S Kobayashi; S Marubashi; Y Takeda; K Dono; K Umeshita; N Matsuura; K Matsubara; Y Doki; M Mori; M Monden Journal: Br J Cancer Date: 2009-04-28 Impact factor: 7.640