482 Enhancement of radiation response by roscovitine in human breast carcinoma in vitro and in vivo xenograft model

Maggiorella, Laurence; Deutsch, E; Frascogna, V.; Bourthis, J.

doi:10.1016/s1359-6349(03)90514-3

Cited by 30 publications

(50 citation statements)

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“…An ability of various pharmacologic Cdk inhibitors to enhance cytotoxicity has been noted in other tumor cell systems and has been correlated to lack of functional p53 protein (30,34). In contrast, the chemosensitizing effect that we report involves both p53 À/À (H1299, HeLa, SW480, and MDA-MB-231) and p53 +/+ (HCT116 and MCF-7) cell lines.…”

Section: Ink4supporting

confidence: 58%

“…We investigated the ability of roscovitine to modulate these two processes in doxorubicin-treated cells. We first confirmed the ability of roscovitine to negatively modulate DNA-PK activity in H1299 cells (30). Then, we investigated the effect of roscovitine on homologous recombination repair.…”

Section: Ink4mentioning

confidence: 71%

“…28), which cooperate in vivo (29). In a previous study (30), the ability of roscovitine to negatively modulate NHEJ pathway in cells treated with ionizing radiation has been reported. Therefore, we analyzed the activity of DNA-PK in H1299 cells treated either with doxorubicin alone or with doxorubicin plus roscovitine.…”

Section: Resultsmentioning

confidence: 88%

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Roscovitine Modulates DNA Repair and Senescence: Implications for Combination Chemotherapy

Crescenzi

Palumbo

Brady

2005

Clinical Cancer Research

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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 doublestrand 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.Chemotherapy is the primary form of treatment for human cancer. Conventional anticancer drugs damage several cellular components, triggering a series of cellular responses. At high doses of these drugs, the predominant effect is cell death, whereas at low doses tumor cells may repair damage and eventually resume normal proliferation (1). Cell death after DNA damage is largely the result of apoptosis, and accordingly, apoptosis is a key determinant of treatment outcome (2). However, although apoptosis represents the main response to chemotherapy in hematologic malignancies, the outcome of therapy in solid tumors does not correlate with the extent of programmed cell death (3). In solid tumors, treatment does not lead to tumor regression but rather results in so-called stable disease. The cytostatic effect of chemotherapeutic agents results from the activation of a premature senescence program (1). Accordingly, treatment of tumor cell lines with low doses of DNA-damaging agents readily induces features of senescence (4). More importantly, the induction of a senescent-like phenotype by anti...

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Section: Ink4supporting

confidence: 58%

Section: Ink4mentioning

confidence: 71%

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Roscovitine Modulates DNA Repair and Senescence: Implications for Combination Chemotherapy

Crescenzi

Palumbo

Brady

2005

Clinical Cancer Research

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“…In consequence, R-roscovitine lead to arrest of tumor cells in almost all cell cycle phases and affected cell proliferation, as it was demonstrated for over 60 human tumor cell lines (e. g., melanoma, lung, breast, colon carcinoma, leukemia). In vivo activity in mice bearing colorectal carcinoma xenografts, but also in hematopoietic progenitors (Mcclue et al, 2002;Raynaud et al, 2005;Song et al, 2007) and enhancement of antitumor effects of radiation and doxorubicin in combination with Rroscovitine was reported (Appleyard et al, 2009;Maggiorella et al, 2003). Like flavopiridol and other Cdk inhibitors with broad spectrum, several additional effects have been described for R-roscovitine in vitro: interruption of transcriptional elongation, interference with survival-associated pathways (IB kinase inhibition), induction of p53 phosphorylation and apoptosis (Alvi et al, 2005;Dey et al, 2008;Hahntow et al, 2004).…”

Section: Overview Of Small Molecule Cdk Inhibitors: Selectivity and Mmentioning

confidence: 99%

Cyclin-Dependent Kinases (Cdk) as Targets for Cancer Therapy and Imaging

Graf¹,

Wuest²,

Pietzsch³

2011

Advances in Cancer Therapy

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“…This treatment caused a reduction in tumour growth of around 95% in two Epstein-Barr Virus (EBV) positive cell lines derived from nasopharyngeal carcinomas [126]. Maggiorella and co-workers also utilised ionising radiation in combination with roscovitine, and achieved an 80% reduction in tumour growth, compared to untreated animals over the 30 days following treatment [130].…”

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confidence: 99%

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

Zhelev

Trifonov²,

Wang³

et al. 2013

Biodiscovery

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This monograph reviews the discovery and development of the cyclindependent kinase inhibitor roscovitine (R-roscovitine, CYC202, Seliciclib). The authors summarise the in vitro and in vivo data that have formed the basis for clinical investigation of Seliciclib as an anti-cancer drug. Kinase selectivity, cellular effects and the pharmacological properties of the drug are discussed in addition to the clinical results of Seliciclib being reviewed. Novel results on the effect of the drug in cardiac hypertrophy are summarized and potential applications of Seliciclib in other therapeutic areas, including, inflammation, virology, glomerulonephritis and polycystic kidney disease, are discussed. Finally the authors argue that optimisation of the therapeutic effect of kinase inhibitors such as Seliciclib can be enhanced using a systems biology approach involving mathematical modelling of the molecular pathways regulating cell growth and division. Seliciclib -discovery and developmentBioDiscovery 2 December 2013 | Issue 10 | 1

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482 Enhancement of radiation response by roscovitine in human breast carcinoma in vitro and in vivo xenograft model

Cited by 30 publications

References 0 publications

Roscovitine Modulates DNA Repair and Senescence: Implications for Combination Chemotherapy

Roscovitine Modulates DNA Repair and Senescence: Implications for Combination Chemotherapy

Cyclin-Dependent Kinases (Cdk) as Targets for Cancer Therapy and Imaging

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

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