Molecular mechanisms of G0/G1 cell-cycle arrest and apoptosis induced by terfenadine in human cancer cells

Jean Dean Liu, Ying Jan Wang, Chien Ho Chen, Cheng Fei Yu, Li Ching Chen, Jen Kun Lin, Yu Chih Liang, Shyr Yi Lin, Yuan Soon Ho

研究成果: 雜誌貢獻文章同行評審

47 引文 斯高帕斯(Scopus)

摘要

Terfenadine (TF), a highly potent histamine H1 receptor antagonist, has been shown to exert no significant central nervous system side effects in clinically effective doses. In this study, we demonstrated that TF induced significant growth inhibition of human cancer cells, including Hep G2, HT 29, and COLO 205 cells, through induction of G0/G1 phase cell-cycle arrest. The minimal dose of TF induced significant G0/G1 arrest in these cells was 1-3 μM. The protein levels of p53, p21/Cip1, and p27/Kip1 were significantly elevated, whereas the kinase activities of cyclin-dependent kinase 2 (CDK2) and CDK4 were inhibited simultaneously in the TF-treated cells. On the other hand, significant apoptosis, but not G0/G1 arrest, was induced in the HL 60 (p53-null) or Hep 3B (with deleted p53) cells when treated with TF (3-5 μM). To clarify the roles of p21/Cip1 and p27/Kip1 protein expression, which was involved in G0/G1 arrest and apoptosis induced by TF in human cancer cells, antisense oligodeoxynucleotides (ODNs) specific to p21/Cip1 and p27/Kip1 were used, and the expression of the p21/Cip1 and p27/Kip1 were monitored by immunoblotting analysis. Our data demonstrated that the percentage of the apoptotic cells detected by annexin V/PI analysis in the TF-treated group was clearly attenuated by pretreatment with p27/Kip1-specific ODNs. These results indicated that p27/Kip1 (but not p21/Cip1) protein indeed played a critical role in the TF-induced apoptosis. We also demonstrated that the TF-induced G0/G1 cell-cycle arrest effect was not reversed by TF removal, and this growth inhibition lasted for at least 7 d. Importantly, the occurrence of apoptosis and cell growth arrest was not observed in the TF-treated normal human fibroblast, even at a dose as high as 25 μM. Our study showed the molecular mechanisms for TF-induced cell growth inhibition and the occurrence of apoptosis in human cancer cells.
原文英語
頁(從 - 到)39-50
頁數12
期刊Molecular Carcinogenesis
37
發行號1
DOIs
出版狀態已發佈 - 五月 1 2003
對外發佈Yes

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

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