The small-molecule CDK inhibitor, SNS-032, enhances cellular radiosensitivity in quiescent and hypoxic non-small cell lung cancer cells

Kodym, Elisabeth; Kodym, Reinhard; Reis, Aimee E.; Habib, Amyn A.; Story, Michael D.; Saha, Debabrata

doi:10.1016/j.lungcan.2008.12.026

Cited by 38 publications

(34 citation statements)

References 49 publications

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“…It has also been suggested that such CDK inhibitors are able to improve the efficacy of other cytotoxic drugs when used in combination [177]. A synergistic benefit has also been described for a second-generation CDK inhibitor (aminothiazole SNS-032), which sensitized radioresistant lung cancer cells to ionizing radiation [175,178]. …”

Section: Cyclin-dependent Kinasesmentioning

confidence: 99%

Prognostic and Predictive Value of Cell Cycle Deregulation in Non-Small-Cell Lung Cancer

2012

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Non-small-cell lung cancer (NSCLC) is among the most frequently diagnosed malignancy and a leading cause for cancer mortality worldwide. Despite various efforts, practical prognostic and predictive markers are still few. We review recent findings concerning the cell cycle in NSCLC and discuss prognostic and predictive aspects as well as the challenge of targeted therapeutic approaches. Deregulation of the cell cycle is a common event in NSCLC. Usually, several defects of cell cycle regulation are concomitant and have a cumulative adverse effect on prognosis. Therefore, analysis of a variety of interacting molecules is desirable for adequate deductions. Immunohistochemical interpretations should include the subcellular staining localization, since this can reflect the functional properties of a protein. Overexpression of cyclins, especially D-type cyclins, has repeatedly been associated with poor prognosis in NSCLC. Predictive data is less conclusive; however, loss of the expression of cyclin-dependent kinase inhibitors seems to correlate with sensitivity to antiproliferative drugs. Various inhibitors of Aurora kinases are currently being evaluated regarding their potential as targeted therapies in NSCLC. In conclusion, the cell cycle offers several prognostic, predictive and therapeutic possibilities in NSCLC, many still developmental. Progress in this field has the potential to improve the current scenario for NSCLC patients.

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Section: Cyclin-dependent Kinasesmentioning

confidence: 99%

Prognostic and Predictive Value of Cell Cycle Deregulation in Non-Small-Cell Lung Cancer

2012

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“…114 First generation compounds to be evaluated in clinical trials included the pan-CDK inhibitor Flavopiridol which induced partial responses or stable disease in patients with NSCLC in a phase I study, when using in combination with the cytotoxic agents paclitaxel and carboplatin. 115 A second-generation CDK inhibitor, the aminothiazole SNS-032 which was recently shown to sensitize radiotherapy-resistant NSCLC cells to ionizing radiation, 116 is currently in phase I clinical trials as an intravenous agent. R-roscovitine (CYC202, seliciclib) is another pan-CDK inhibitor which has antitumor activity against a broad range of cancer cell lines and human cancer xenografts including NSCLC.…”

Section: Alteration Of the Components Of Cell Cycle Checkpoints In Lumentioning

confidence: 99%

Role of cell cycle regulators in lung carcinogenesis

Eymin

Gazzéri

2010

Cell Adhesion & Migration

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“…Over the past three decades, few studies have compared the difference in the response to the external stimuli of resting and proliferating human PBLs [3,4] , and some studies just used the traditional alkaline comet assay to simply measure DNA damage in epidemiological studies [5][6][7] . A member of the histone H2A family, H2AX, was incorporated into nucleosomes and involved in the formation of DNA structure [8] .…”

Section: Discussionmentioning

confidence: 99%

DNA damage response in resting and proliferating peripheral blood lymphocytes treated by camptothecin or X-ray

Tian

Feng

Jiang

et al. 2011

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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DNA damage response (DDR) in different cell cycle status of human peripheral blood lymphocytes (PBLs) and the role of H2AX in DDR were investigated. The PBLs were stimulated into cell cycle with phytohemagglutinin (PHA). The apoptotic ratio and the phosphorylation H2AX (S139) were flow cytometrically measured in resting and proliferating PBLs after treatment with camptothecin (CPT) or X-ray. The expressions of γH2AX, Bcl-2, caspase-3 and caspase-9 were detected by Western blotting. DDR in 293T cells was detected after H2AX was silenced by RNAi method. Our results showed that DNA double strand breaks (DSBs) were both induced in quiescent and proliferating PBLs after CPT or X-ray treatment. The phosphorylation of H2AX and apoptosis were more sensitive in proliferating PBLs compared with quiescent lymphocytes (P<0.05). The expression levels of anti-apoptotic proteins Bcl-2 were reduced and cleaved caspase-3 and caspase-9 were increased. No significant changes were observed in CPT-induced apoptosis in 293T cells between H2AX knocking down group and controls. It was concluded that proliferating PBLs were more vulnerable to DNA damage compared to non-stimulated lymphocytes and had higher apoptosis rates. γH2AX may only serve as a marker of DNA damage but exert no effect on apoptosis regulation.

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The small-molecule CDK inhibitor, SNS-032, enhances cellular radiosensitivity in quiescent and hypoxic non-small cell lung cancer cells

Cited by 38 publications

References 49 publications

Prognostic and Predictive Value of Cell Cycle Deregulation in Non-Small-Cell Lung Cancer

Prognostic and Predictive Value of Cell Cycle Deregulation in Non-Small-Cell Lung Cancer

Role of cell cycle regulators in lung carcinogenesis

DNA damage response in resting and proliferating peripheral blood lymphocytes treated by camptothecin or X-ray

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