Is olomoucine, a weak CDK2 inhibitor, able to induce apoptosis in cancer cells?
Olomoucine (OLO), a substituted purine analogue, is a much weaker inhibitor of cyclin-dependent kinases than other closely related ATP derivatives. It has been recently reported that OLO did not affect the viability of normal human MRC-5 fibroblasts, but it inhibited the proliferation of human HL-60 leukemia cells. Therefore, it was interesting to explore the antiproliferative effect of OLO and to characterize its action on distinct human cancer cells differing in the functional status of the cell cycle. Human HeLa cervical carcinoma and HL-60 leukemia cells were continuously exposed to increasing concentrations of OLO for 24 h and 48 h or alternatively, cells after treatment for 24 h were postincubated in a drug-free medium. Surprisingly, OLO more strongly affected the proliferation of HL-60 cells than that of HeLa cells. Flow cytometric analyses revealed that OLO at higher doses increases the frequency of a hypoploid HL-60 cell population representing cells undergoing apoptosis. These results substantiated the data of the determination of the number of viable cells. Moreover, OLO at higher doses modulates the cell cycle progression of tested cancer cells. Detailed analyses of the DNA concentration in single cells revealed that OLO-mediated reduction of the number of G(1)-phase cells was accompanied by an increase of the frequency of G(2)-phase cells. The kinetics of these changes differed between both tested cancer cell lines, suggesting that some cancer cells exhibit increased susceptibility to OLO action. It remains to clarify whether the strong proapoptotic effect of OLO observed in HL-60 cells depends on their differentiation status.
Wandl
Stefanie
S
Cell Cycle Regulation Group, Division Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
Wesierska-Gadek
Józefa
J
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016193:G1 Phase / Q000235:genetics; D016195:G2 Phase / Q000187:drug effects; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007701:Kinetin / Q000494:pharmacology*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D016196:S Phase / Q000187:drug effects
D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; C090046:olomoucine; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D053148:Caspase 3; D053179:Caspase 7; D007701:Kinetin