Sodium butyrate (NaBt), a physiologically occurring
short-chain fatty acid, induces differentiation as well as apoptosis in numerous cell types, and this induction is partially regulated by Bcl-2 expression. The objectives of our study were to characterize the in vitro effects of NaBt and/or
docetaxel on the growth, cell cycle and apoptosis of human
bladder cancer cells, and to determine whether
tumor growth in vivo is inhibited by
isobutyramide, an orally bioavailable Bt analogue, and/or
docetaxel by using Bcl-2-transfected human
bladder cancer cell line KoTCC-1/BH and control vector only-transfected cell line KoTCC-1/C. NaBt caused a decrease in growth of both KoTCC-1/C and KoTCC-1/BH cells, however, its growth inhibitory effect was significantly greater in KoTCC-1/C cells. One mM NaBt resulted in G1 cell cycle arrest, accompanied by up-regulation of p21 (waf1/cip1) and down-regulation of
cyclin D1 in KoTCC-1/C cells, whereas KoTCC-1/BH showed resistance to G1 cell cycle arrest. An amount of 5 mM NaBt induced apoptosis, accompanied by up-regulation of Bak in KoTCC-1/C cells but failed to induce apoptosis in KoTCC-1/BH cells despite substantial down-regulation of Bcl-2.
Oral administration of
isobutyramide significantly reduced the KoTCC-1/C
tumor volume compared with the KoTCC-1/BH
tumor volume in nude mice. Furthermore,
docetaxel induced Bcl-2 phosphorylation in KoTCC-1/BH cells and combined treatment with
isobutyramide and
docetaxel synergistically inhibited the growth of KoTCC-1/BH cells both in vitro and in vivo. These findings suggest that
isobutyramide therapy could be a novel therapeutic strategy for patients with
bladder cancer if
docetaxel is combined according to the Bcl-2 expression status.