Modulation of docetaxel-induced apoptosis and cell cycle arrest by all-trans retinoic acid in prostate cancer cells

We report that all-trans retinoic acid (ATRA) enhanced the toxicity of doce taxel against DU145 and LNCaP prostate cancer cells, and that the nature of the interaction between ATRA and docetaxel was highly synergistic. Docetax el-induced apoptotic cell death was associated with phosphorylation and hen ce inactivation of Bcl-2. ATRA enhanced docetaxel-induced apoptosis and com bined treatment with ATRA and docetaxel resulted in down-regulation of Bcl- 2. Docetaxel caused phosphorylation and hence inactivation of cdc2 kinase r esulting in G2/M arrest. ATRA inhibited docetaxel-induced phosphorylation o f cdc2 resulting in activation of cdc2 kinase and partial reversal of the G 2/M arrest. ATRA also inhibited docetaxel-induced activation of MAPK indica ting that the effects of docetaxel and ATRA on cdc2 phosphorylation are dep endent on MAPK. We conclude that ATRA synergistically enhances docetaxel to xicity by down-regulating Bcl-2 expression and partially reverses the docet axel-induced G2/M arrest by inhibiting docelaxel-induced cdc2 phosphorylati on in a pathway that is dependent on MAPK. (C) 2001 Cancer Research Campaig n.