Synergic effects of the cyclin-dependent kinase (CDK) inhibitor olomoucine and androgen-antagonist bicalutamide on prostatic cancer cell lines.
Currently, mechanisms leading to both apoptosis induction and the development of hormone-independence of prostate carcinoma cells are intensively studied. Attention is also given to the possibility of restoring cell sensitivity to hormone-antagonists. The present study focuses on the effect of the combined synthetic cyclin-dependent kinase [CDK] inhibitor, olomoucine and the antiandrogen bicalutamide on hormone-insensitive (DU-145) and hormone-sensitive (LNCaP) prostate cancer cell lines. In both cell lines reduction in cell viability was significantly higher when olomoucine and bicalutamide were applied in combination when compared to separate application of both these drugs. The setting of optimal concentrations for both substances was important for the final effect on both cell lines. The proliferation arrest was accompanied by a decrease in cyclin D1 expression and the activation of p21Waf1/Cip1 and p27Kip1 pathways in both cell lines. Contrary to the previously described effect of 200 microM olomoucine, weak AR induction after treatment with effective concentrations of olomoucine was not seen in the hormone- insensitive cell line DU-145. The related reaction of DU-145 and LNCaP cell lines to treatment with combined olomoucine and bicalutamide likely provides evidence that the inhibitory effect of bicalutamide may not only be associated with its antiandrogenic properties. The tested substances probably influence different regulatory pathways and these have co-operative impact on the cell cycle outcome. Understanding antitumor and antihormone actions of both agents is essential for the development of novel therapeutic schemes integrating substances with different action. Our results show that the combination of synthetic CDK inhibitors and hormone- antagonists may be one of a number of possible alternatives.
Knillová
J
J
Institute of Pathology, Laboratory of Molecular Pathology, Faculty of Medicine, Palacky University, CZ-77515 Olomouc, Czech Republic.
Bouchal
J
J
Hlobilková
A
A
Strnad
M
M
Kolár
Z
Z
D000726:Androgen Antagonists / Q000633:toxicity*; D000813:Anilides / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000633:toxicity; D006801:Humans; D007701:Kinetin; D008297:Male; D009570:Nitriles; D011471:Prostatic Neoplasms; D011687:Purines / Q000633:toxicity; D014105:Tosyl Compounds
D000726:Androgen Antagonists; D000813:Anilides; D004791:Enzyme Inhibitors; D009570:Nitriles; D011687:Purines; D014105:Tosyl Compounds; C090046:olomoucine; C053541:bicalutamide; D018844:Cyclin-Dependent Kinases; D007701:Kinetin