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 docetaxel against DU145 and LNCaP prostate cancer cells, and that the nature of the interaction between ATRA and docetaxel was highly synergistic. Docetaxel-induced apoptotic cell death was associated with phosphorylation and hence inactivation of Bcl-2. ATRA enhanced docetaxel-induced apoptosis and combined treatment with ATRA and docetaxel resulted in down-regulation of Bcl-2. Docetaxel caused phosphorylation and hence inactivation of cdc2 kinase result ing in G2/M arrest. ATRA inhibited docetaxel-induced phosphorylation of cdc2 resulting in activation of cdc2 kinase and partial reversal of the G2/M arrest. ATRA also inhibited docetaxel-induced activation of MAPK indicating that the effects of docetaxel and ATRA on cdc2 phosphorylation are dependent on MAPK. We conclude that ATRA synergistically enhances docetaxel toxicity by down-regulating Bcl-2 expression and partially reverses the docetaxel-induced G2/M arrest by inhibiting docetaxel-induced cdc2 phosphorylation in a pathway that is dependent on MAPK.
Nehmé
A
A
Department of Medicine and the Cancer Center, University of California, 9500 Gilman Drive, San Diego, La Jolla, CA 92093-0058, USA.
Varadarajan
P
P
Sellakumar
G
G
Gerhold
M
M
Niedner
H
H
Zhang
Q
Q
Lin
X
X
Christen
R D
RD
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D019938:Cyclin D1 / Q000096:biosynthesis; D000077143:Docetaxel; D015536:Down-Regulation; D004347:Drug Interactions; D006801:Humans; D008297:Male; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D043823:Taxoids; D014212:Tretinoin / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D019938:Cyclin D1; D000077143:Docetaxel; D014212:Tretinoin; D017239:Paclitaxel