Functional p53 in cells contributes to the anticancer effect of the cyclin-dependent kinase inhibitor roscovitine.
Inhibitors of cyclin-dependent kinases (CDKs) undergoing clinical trials as anticancer agents usually target several CDKs in cells. Some of them are also able to increase cellular levels of p53 protein and to activate p53-regulated transcription. To define the role of p53 in the anticancer effect of selective CDK inhibitors, two related compounds roscovitine and olomoucine II were studied. Roscovitine differs functionally from its congener olomoucine II only in the selectivity towards transcriptional CDK9. Action of both compounds on proliferation, cell-cycle progression, and apoptosis was examined in RPMI-8226 cells expressing the temperature-sensitive mutant of p53 and in MCF-7 cells with wild-type p53. Both compounds blocked proliferation, decreased phosphorylation of RNA polymerase II, downregulated antiapoptotic protein Mcl-1 in both cell lines in a dose-dependent manner, and also activated p53 in MCF-7 cells. Moreover, we showed that the anticancer efficiency of CDK inhibitors was enhanced by active p53 in RPMI-8226 cells kept at permissive temperature, where downregulation of Mcl-1, fragmentation of PARP-1, and increased caspase-3 activity was detected with lower doses of the compounds. The results confirm that functional p53 protein may enhance the anticancer activity of roscovitine that could be beneficial for anticancer therapy.
Paprskárová
Martina
M
Laboratory of Growth Regulators, Faculty of Science, Palacký University & Institute of Experimental Botany, 783 71 Olomouc, Czech Republic.
Krystof
Vladimír
V
Jorda
Radek
R
Dzubák
Petr
P
Hajdúch
Marián
M
Wesierska-Gadek
Józefa
J
Strnad
Miroslav
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D012319:RNA Polymerase II / Q000378:metabolism; D000077546:Roscovitine; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011687:Purines; D016159:Tumor Suppressor Protein p53; C475587:olomoucine II; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II; D020169:Caspases