Induction of cell-cycle arrest and apoptosis by a novel retinobenzoic- acid derivative, TAC-101, in human pancreatic-cancer cells

Koji Fujimoto, Ryo Hosotani, Ryuichiro Doi, Michihiko Wada, Jeon Uk Lee, Takatomo Koshiba, Yoshiharu Miyamoto, Shoichiro Tsuji, Sanae Nakajima, Masayuki Imamura

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)637-644
Number of pages8
JournalInternational Journal of Cancer
Volume81
Issue number4
DOIs
Publication statusPublished - 10-05-1999

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Cell Cycle Checkpoints
Pancreatic Neoplasms
Apoptosis
Acids
G1 Phase
Phosphorylation
TAC 101
Cyclin-Dependent Kinase Inhibitor p21
Retinoblastoma Genes
G1 Phase Cell Cycle Checkpoints
Cyclin A
Cyclin E
Thymidylate Synthase
Cyclins
Growth
Tretinoin
Electrophoresis
Up-Regulation
Gels
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Fujimoto, Koji ; Hosotani, Ryo ; Doi, Ryuichiro ; Wada, Michihiko ; Lee, Jeon Uk ; Koshiba, Takatomo ; Miyamoto, Yoshiharu ; Tsuji, Shoichiro ; Nakajima, Sanae ; Imamura, Masayuki. / Induction of cell-cycle arrest and apoptosis by a novel retinobenzoic- acid derivative, TAC-101, in human pancreatic-cancer cells. In: International Journal of Cancer. 1999 ; Vol. 81, No. 4. pp. 637-644.
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abstract = "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.",
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Induction of cell-cycle arrest and apoptosis by a novel retinobenzoic- acid derivative, TAC-101, in human pancreatic-cancer cells. / Fujimoto, Koji; Hosotani, Ryo; Doi, Ryuichiro; Wada, Michihiko; Lee, Jeon Uk; Koshiba, Takatomo; Miyamoto, Yoshiharu; Tsuji, Shoichiro; Nakajima, Sanae; Imamura, Masayuki.

In: International Journal of Cancer, Vol. 81, No. 4, 10.05.1999, p. 637-644.

Research output: Contribution to journalArticle

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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

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