Pleiotropic effects of selective CDK inhibitors on human normal and cancer cells

Escape from the proper control of the cell cycle by up-regulation of cyclins or aberrant activation of cyclin-dependent kinases (CDKs) as well as by inactivation of cellular inhibitors of CDKs (CKI) leads to malignant transformation. Loss of cellular CKIs in cancers provided a rationale for development of pharmacological inhibitors of CDKs. Recently synthesized CKIs, e.g., purine derivatives such as olomoucine (OLO) and roscovitine (ROSC) are non-genotoxic and exhibit increased selectivity towards CDK2 and CDK7/9. Interestingly, both drugs induce additional effects. Recently, a new, unexpected action of OLO on normal human cells was observed. OLO strongly up-regulates CLIMP-63, a 65 kD protein that mediates the anchoring of the ER to microtubules. Moreover, ROSC induces in human MCF-7 cells phosphorylation of p53 protein at Ser-46 which in turn initiates caspase-independent apoptosis. In the present contribution we raised the question whether both CKIs would be able to block cell cycle progression and to reactivate p53 protein in human HPV-positive HeLa cervix carcinoma cells. We also addressed the question whether exponentially growing cancer cells are more susceptible to the inhibitory action of CKIs than normal cells. Our results show that HeLa cells are much more sensitive to ROSC than normal fibroblasts. ROSC induces G(2) arrest and apoptosis in HeLa cells. It also reactivates and stabilizes wt p53 protein. The increase of p53 protein coincides with down-regulation of E6 oncoprotein. Thus, the biological action of substituted purines is not restricted to the inhibition of CDKs and open new perspectives for their therapeutic applications.