Roscovitine modulates DNA repair and senescence: implications for combination chemotherapy.
Crescenzi, Elvira ; Palumbo, Giuseppe ; Brady, Hugh J M ; - ASI Sponsor
Nov - 2005
DOI: 10.1158/1078-0432.CCR-05-1042
ISSN : 1078-0432 ;
journal : Clinical cancer research : an official journal of the American Association for Cancer Research

Issue : 22
type: Article Journal

Abstract
PURPOSE: Treatment of tumor cells by chemotherapy activates a series of responses ranging from apoptosis to premature senescence and repair. Survival responses are characterized by inhibition of cyclin-dependent kinases. Because inhibition of cyclin-dependent kinases represents a distinctive feature of DNA damage-induced prosurvival responses, we investigated the possibility that the cyclin-dependent kinase inhibitor roscovitine modulates drug-induced responses in human adenocarcinoma cells, favoring cell survival. EXPERIMENTAL DESIGN: Sublethal concentrations of doxorubicin were used to induce premature senescence in human adenocarcinoma cells. The effect of the cyclin-dependent kinase inhibitor roscovitine on the doxorubicin-dependent cell cycle checkpoint activation and DNA repair pathways was evaluated. RESULTS: Roscovitine reinforces doxorubicin-dependent G(1) checkpoint in A549 and HEC1B cells leading to decreased frequency of double-strand breaks and to the preferential induction of senescence and enhanced clonogenic survival. However, in other tumor cell lines, such as HCT116 and H1299, combined treatment with doxorubicin and roscovitine increases the frequency of double-strand breaks and dramatically sensitizes to doxorubicin. This unexpected effect of roscovitine depends on a novel ability to inhibit DNA double-strand break repair processes and requires inactivation of the pRb pathway. CONCLUSIONS: Roscovitine, by hindering DNA repair processes, has the potential to inhibit recovery of mildly damaged tumor cells after doxorubicin treatment and to increase the susceptibility of tumor cells to chemotherapy. However, in some tumor cells, the cell cycle inhibitory function of roscovitine prevails over the DNA repair inhibitory activity, favoring premature senescence and clonogenic growth. These data indicate a novel mechanism underlying combined chemotherapy, which may have wide application in treatment of carcinomas.

keywords : Antineoplastic Agents,Antineoplastic Agents: pharmacology,Cell Aging,Cell Aging: drug effects,Cell Line,Cell Proliferation,Cell Proliferation: drug effects,Cell Survival,Cell Survival: drug effects,Cyclin-Dependent Kinases,Cyclin-Dependent Kinases: antagonists \& inhibitors,Cyclin-Dependent Kinases: metabolism,DNA Damage,DNA Damage: drug effects,DNA Repair,DNA Repair: drug effects,Doxorubicin,Doxorubicin: pharmacology,Drug Synergism,Etoposide,Etoposide: pharmacology,G1 Phase,G1 Phase: drug effects,G2 Phase,G2 Phase: drug effects,Humans,Purines,Purines: pharmacology,Retinoblastoma Protein,Retinoblastoma Protein: metabolism,Time Factors,Tumor