Sodium butyrate induces apoptosis in human renal cell carcinoma cells and synergistically enhances their sensitivity to anti-Fas-mediated cytotoxicity.
Sodium butyrate (NaBt), one of the short chain fatty acids naturally formed in the gastrointestinal tract, induces differentiation as well as apoptosis in numerous cell types. The objectives of this study were to characterize the effects of NaBt on the growth, cell cycle, and apoptosis of human renal cell carcinoma (RCC) cells, and to determine whether NaBt enhances the Fas-mediated cytotoxicity in these cells. NaBt reduced the in vitro growth rate of human RCC ACHN cells in a time- and dose-dependent manner. Treatment of ACHN cells with 1 mM NaBt resulted in G1 cell cycle arrest, accompanied by up-regulation of p21 (waf1/cip1) and down-regulation of cyclin D1. In contrast, 5 mM NaBt-induced apoptotic cell death in ACHN cells, accompanied by up-regulation of BaK and down-regulation of Bcl-2. Furthermore, NaBt synergistically enhanced the growth-inhibitory effect of anti-Fas monoclonal antibody, CH11 on CH11-sensitive ACHN cells, and apoptotic cell death was induced by the combination of sublethal doses of NaBt and CH11, but not by either agent alone. Similar synergy was also observed in CH11-resistant human RCC KN39 cells. These findings suggest that NaBt could be a novel attractive approach for patients with RCC, and that the efficacy of NaBt may be enhanced by the combined use of Fas-mediated therapy.
Hara
I
I
Department of Urology, Kobe University School of Medicine, Kobe 650-0017, Japan. hara@med.kobe-u.ac.jp
Miyake
H
H
Hara
S
S
Arakawa
S
S
Kamidono
S
S
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D053938:DNA Fragmentation; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002087:Butyrates; D009363:Neoplasm Proteins; D019014:fas Receptor