TY - JOUR
T1 - Induction of cell-cycle arrest and apoptosis by a novel retinobenzoic- acid derivative, TAC-101, in human pancreatic-cancer cells
AU - Fujimoto, Koji
AU - Hosotani, Ryo
AU - Doi, Ryuichiro
AU - Wada, Michihiko
AU - Lee, Jeon Uk
AU - Koshiba, Takatomo
AU - Miyamoto, Yoshiharu
AU - Tsuji, Shoichiro
AU - Nakajima, Sanae
AU - Imamura, Masayuki
PY - 1999
Y1 - 1999
N2 - In this study, we investigated the effect of a novel retinobenzoic acid, 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101), on the growth of 4 human pancreatic-cancer cell lines; BxPC-3, MIA-PaCa-2, CFPAC-1 and AsPC-1, TAC-101 significantly inhibited the proliferation of BxPC-3 and MIA- PaCa-2 cells in a time- and concentration-dependent manner, but not the proliferation of AsPC-1 cells. Furthermore, the anti-proliferative effects of TAC-101 on BxPC-3 and MIA-PaCa-2 cells were stronger than those of all-trans retinoic acid. Flow-cytometric analyses indicated that treatment of BxPC-3 with TAC-101 strongly induces cell-cycle arrest at the G1 phase. The cell- cycle arrest induced by TAC-101 was accompanied by reduction of retinoblastoma-gene product (RB) phosphorylation and an increase of 2 cyclin- dependent kinase (CDK) inhibitors, p21(WAF1/Cip1) (p21) and p27(Kip1) (p27). TAC-101 also caused a decrease in cyclin A and thymidylate synthase, which are E2F-regulated gene products. No changes were observed in the expression of cyclin DI, cyclin E on CDK2. In addition, Hoechst staining, gel electrophoresis and flow-cytometric analysis indicated that a marked reduction in the number of BxPC-3 cells with TAC-101 was related to the induction of apoptosis. Our results suggest that TAC-101 inhibits the growth of certain pancreatic-cancer cells by means of G1-phase cell-cycle arrest resulting from the reduction of RB phosphorylation and the up-regulation of p21 and p27 as well as the induction of apoptosis. TAC-101 may therefore be a useful agent for new therapeutic strategies focusing on inhibition of pancreatic-cancer-cell proliferation.
AB - In this study, we investigated the effect of a novel retinobenzoic acid, 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101), on the growth of 4 human pancreatic-cancer cell lines; BxPC-3, MIA-PaCa-2, CFPAC-1 and AsPC-1, TAC-101 significantly inhibited the proliferation of BxPC-3 and MIA- PaCa-2 cells in a time- and concentration-dependent manner, but not the proliferation of AsPC-1 cells. Furthermore, the anti-proliferative effects of TAC-101 on BxPC-3 and MIA-PaCa-2 cells were stronger than those of all-trans retinoic acid. Flow-cytometric analyses indicated that treatment of BxPC-3 with TAC-101 strongly induces cell-cycle arrest at the G1 phase. The cell- cycle arrest induced by TAC-101 was accompanied by reduction of retinoblastoma-gene product (RB) phosphorylation and an increase of 2 cyclin- dependent kinase (CDK) inhibitors, p21(WAF1/Cip1) (p21) and p27(Kip1) (p27). TAC-101 also caused a decrease in cyclin A and thymidylate synthase, which are E2F-regulated gene products. No changes were observed in the expression of cyclin DI, cyclin E on CDK2. In addition, Hoechst staining, gel electrophoresis and flow-cytometric analysis indicated that a marked reduction in the number of BxPC-3 cells with TAC-101 was related to the induction of apoptosis. Our results suggest that TAC-101 inhibits the growth of certain pancreatic-cancer cells by means of G1-phase cell-cycle arrest resulting from the reduction of RB phosphorylation and the up-regulation of p21 and p27 as well as the induction of apoptosis. TAC-101 may therefore be a useful agent for new therapeutic strategies focusing on inhibition of pancreatic-cancer-cell proliferation.
UR - http://www.scopus.com/inward/record.url?scp=0032959825&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032959825&partnerID=8YFLogxK
U2 - 10.1002/(SICI)1097-0215(19990517)81:4<637::AID-IJC21>3.0.CO;2-4
DO - 10.1002/(SICI)1097-0215(19990517)81:4<637::AID-IJC21>3.0.CO;2-4
M3 - Article
C2 - 10225456
AN - SCOPUS:0032959825
SN - 0020-7136
VL - 81
SP - 637
EP - 644
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 4
ER -
