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Induction of cell‐cycle arrest and apoptosis by a novel retinobenzoic‐acid derivative, TAC‐101, in human pancreatic‐cancer cells
Author(s) -
Fujimoto Koji,
Hosotani Ryo,
Doi Ryuichiro,
Wada Michihiko,
Lee JeonUk,
Koshiba Takatomo,
Miyamoto Yoshiharu,
Tsuji Shoichiro,
Nakajima Sanae,
Imamura Masayuki
Publication year - 1999
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19990517)81:4<637::aid-ijc21>3.0.co;2-4
Subject(s) - cell cycle , cyclin d1 , apoptosis , cancer research , chemistry , cell growth , cell cycle checkpoint , microbiology and biotechnology , cyclin e , pancreatic cancer , biology , medicine , biochemistry , cancer
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, MIAPaCa‐2, CFPAC‐1 and AsPC‐1. TAC‐101 significantly inhibited the proliferation of BxPC‐3 and MIAPaCa‐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 MIAPaCa‐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 G 1 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 D1, 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 G 1 ‐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. Int. J. Cancer 81:637–644, 1999. © 1999 Wiley‐Liss, Inc.