The use of histone deacetylase inhibitor FK228 and DNA hypomethylation agent 5-azacytidine in human bladder cancer therapy

Jose A. Karam, Jinhai Fan, Jennifer Stanfield, Edmond Richer, Elie A. Benaim, Eugene P Frenkel, Peter Antich, Arthur I Sagalowsky, Ralph P Mason, Jer-Tsong Hsieh

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

The long-term disease-free survival in patients with metastatic transitional cell carcinoma (TCC) is still considerably low. Novel chemotherapeutic agents are needed to decrease the morbidity and mortality of TCC. In this study, we have evaluated several epigenetic modifiers for their therapeutic application in bladder cancer. Both histone deacetylase inhibitors (FK228, TSA) and DNA hypomethylating agent (5-Azacytidine) were tested using in vitro assays such as cell viability, cell cycle analysis and western blot to determine their mechanisms of action. Drug combination experiments were also designed to study any additive or synergistic effects of these agents. In addition, two bladder cancer xenograft models (one subcutaneous and one orthotopic) were employed to assess the therapeutic efficacy of these agents in vivo. Three agents exhibited various growth inhibitory effects on 5 different TCC cell lines in a dose- and time-dependent manner. In addition to G 2/M cell cycle arrest, FK228 is more potent in inducting apoptosis than the two other single agents, and combination of both FK228 and 5-Aza further enhances this effect. p21 induction is closely associated with FK228 or TSA but not 5-Aza, which is mediated via p53-independent pathway. Consistent with in vitro results, FK228 exhibited a significant in vivo growth inhibition of TCC tumor in both subcutaneous and orthotopic xenograft models. FK228 is a potent chemotherapeutic agent for TCC in vivo with minimal undesirable side effects. The elevated p21 level mediated via p53 independent pathway is a hallmark of FK228 mechanism of action.

Original languageEnglish (US)
Pages (from-to)1795-1802
Number of pages8
JournalInternational Journal of Cancer
Volume120
Issue number8
DOIs
StatePublished - Apr 15 2007

Keywords

  • Bladder cancer
  • Chemotherapy
  • DNA methylation
  • Histone acetylation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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