G2 Checkpoint Kinase Inhibitors Exert Their Radiosensitizing Effects Prior to the G2/M Transition

Sturgeon, Christopher M.; Roberge, Michel

doi:10.4161/cc.6.5.3926

Cited by 9 publications

(4 citation statements)

References 32 publications

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“…3). The results from our cell cycle studies are in accordance with the recent study of Sturgeon and Roberge (28) who showed in a very comprehensive analysis that caffeine was only able to radiosensitize breast cancer cell lines if given at the time when most cells progress from G 1 into S phase rather than at the time of maximal G 2 arrest. Furthermore, our results are in line with the study of Deplanque et al (29) who showed in the model of normal human skin fibroblasts that the radiosensitizing effect of caffeine was associated with modulation of G 1 rather than G 2 checkpoint.…”

Section: Discussionsupporting

confidence: 81%

Caffeine Confers Radiosensitization of PTEN-Deficient Malignant Glioma Cells by Enhancing Ionizing Radiation–Induced G1 Arrest and Negatively Regulating Akt Phosphorylation

Sinn

Tallen²,

Schroeder³

et al. 2010

Molecular Cancer Therapeutics

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PTEN mutations are frequently found in malignant glioma and can result in activated phosphatidylinositol-3-kinase/Akt survival signaling associated with resistance to radiotherapy. Strategies to interfere with aberrant PI3K/Akt activity are therefore being developed to improve the therapeutic efficacy of radiotherapy in patients with malignant glioma. The methylxanthine caffeine has been described as a PI3K inhibitor and is also known to sensitize cells to ionizing radiation. However, a direct association between these two caffeinemediated effects has not been reported yet. Therefore, we asked whether caffeine or its derivative pentoxifylline differentially affect the radiosensitivity of malignant gliomas with different PTEN status. As models, we used the radiosensitive EA14 malignant glioma cell line containing wild-type PTEN and the radioresistant U87MG malignant glioma cell line harboring mutant PTEN. Our study revealed that caffeine and pentoxifylline radiosensitized PTEN-deficient but not PTEN-proficient glioma cells. Radiosensitization of PTENdeficient U87MG cells by caffeine was significantly correlated with the activation of the G 1 DNA damage checkpoint that occurred independently of de novo synthesis of p53 and p21. The p53 independency was also confirmed by a significant caffeine-mediated radiosensitization of the glioma cell lines T98G and U373MG that are deficient for both PTEN and p53. Furthermore, caffeine-mediated radiosensitization was associated with the inhibition of Akt hyperphosphorylation in PTEN-deficient cells to a level comparable with PTEN-proficient cells. Our data suggest that the methylxanthine caffeine or its derivative pentoxifylline are promising candidate drugs for the radiosensitization of glioma cells particularly with PTEN mutations. Mol Cancer Ther; 9(2); 480-8. ©2010 AACR.

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Section: Discussionsupporting

confidence: 81%

Caffeine Confers Radiosensitization of PTEN-Deficient Malignant Glioma Cells by Enhancing Ionizing Radiation–Induced G1 Arrest and Negatively Regulating Akt Phosphorylation

Sinn

Tallen²,

Schroeder³

et al. 2010

Molecular Cancer Therapeutics

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“…This is potentially applicable to treatment modalities to which S-phase cells are particularly vulnerable, for example, radiotherapy. In support of this and the notion that G 2 -M bypass is dispensable for synergy, radiosensitization has been reported to occur most optimally when CHK1 is inhibited during S-phase, but not when G 2 -M abrogation is maximal (37). Attractive concepts on chemoradiosensitization with checkpoint kinase inhibitors have been proposed but remain largely unexplored (10).…”

Section: Discussionmentioning

confidence: 93%

CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus

et al. 2015

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Combining cell-cycle checkpoint kinase inhibitors with the DNA-damaging chemotherapeutic agent gemcitabine offers clinical appeal, with a mechanistic rationale based chiefly on abrogation of gemcitabine-induced G 2 -M checkpoint activation. However, evidence supporting this mechanistic rationale from chemosensitization studies has not been consistent. Here we report a systematic definition of how pancreatic cancer cells harboring mutant p53 respond to this combination therapy, by combining mathematical models with large-scale quantitative biologic analyses of single cells and cell populations. Notably, we uncovered a dynamic range of mechanistic effects at different ratios of gemcitabine and CHK1 inhibitors. Remarkably, effective synergy was attained even where cells exhibited an apparently functional G 2 -M surveillance mechanism, as exemplified by a lack of both overt premature CDK1 activation and S-phase mitotic entry. Consistent with these findings, S-G 2 duration was extended in treated cells, leading to a definable set of lineage-dependent catastrophic fates. At synergistic drug concentrations, global replication stress was a distinct indicator of chemosensitization as characterized molecularly by an accumulation of S-phase cells with high levels of hyperphosphorylated RPA-loaded single-stranded DNA. In a fraction of these cells, persistent genomic damage was observed, including chromosomal fragmentation with a loss of centromeric regions that prevented proper kinetochore-microtubule attachment. Together, our results suggested a "foot-in-the-door" mechanism for drug synergy where cells were destroyed not by frank G 2 -M phase abrogation but rather by initiating a cumulative genotoxicity that deregulated DNA synthesis. Cancer Res; 75(17); 3583-95. Ó2015 AACR.

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“…Ataxia-telangiectasia mutated (ATM) protein is an important signal transducer of the DNA damage response, which contains DNA repair and cell cycle checkpoints, and activation of ATM by autophosphorylation occurs in response to exposed DNA DSBs (5). Cells mutated in the ATM gene have defects in cell cycle checkpoints and DNA repair and are hypersensitive to DSBs (6, 7); thus, agents that inhibit the ATM pathway can be useful radiosensitizers (8). The Mre11, Rad50, and NBS1 (MRN) complex is quickly stimulated by DSBs and directly activates ATM (9,10).…”

Section: Introductionmentioning

confidence: 99%

Telomerase-Dependent Oncolytic Adenovirus Sensitizes Human Cancer Cells to Ionizing Radiation via Inhibition of DNA Repair Machinery

et al. 2010

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The inability to repair DNA double-strand breaks (DSB) leads to radiosensitization, such that ionizing radiation combined with molecular inhibition of cellular DSB processing may greatly affect treatment of human cancer. As a variety of viral products interact with the DNA repair machinery, oncolytic virotherapy may improve the therapeutic window of conventional radiotherapy. Here, we describe the mechanistic basis for synergy of irradiation and OBP-301 (Telomelysin), an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 infection led to E1B55kDa viral protein expression that degraded the complex formed by Mre11, Rad50, and NBS1, which senses DSBs. Subsequently, the phosphorylation of cellular ataxia-telangiectasia mutated protein was inhibited, disrupting the signaling pathway controlling DNA repair. Thus, tumor cells infected with OBP-301 could be rendered sensitive to ionizing radiation. Moreover, by using noninvasive whole-body imaging, we showed that intratumoral injection of OBP-301 followed by regional irradiation induces a substantial antitumor effect, resulting from tumor cell-specific radiosensitization, in an orthotopic human esophageal cancer xenograft model. These results illustrate the potential of combining oncolytic virotherapy and ionizing radiation as a promising strategy in the management of human cancer. Cancer Res; 70(22); 9339-48. ©2010 AACR.

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G2 Checkpoint Kinase Inhibitors Exert Their Radiosensitizing Effects Prior to the G2/M Transition

Cited by 9 publications

References 32 publications

Caffeine Confers Radiosensitization of PTEN-Deficient Malignant Glioma Cells by Enhancing Ionizing Radiation–Induced G1 Arrest and Negatively Regulating Akt Phosphorylation

Caffeine Confers Radiosensitization of PTEN-Deficient Malignant Glioma Cells by Enhancing Ionizing Radiation–Induced G1 Arrest and Negatively Regulating Akt Phosphorylation

CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus

Telomerase-Dependent Oncolytic Adenovirus Sensitizes Human Cancer Cells to Ionizing Radiation via Inhibition of DNA Repair Machinery

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