Identification and Characterization of a Small Inhibitory Peptide That Can Target DNA-PKcs Autophosphorylation and Increase Tumor Radiosensitivity

Sun, Xin; Yang, Chunying; Lü, Hai; Wang, Qi; Wu, Shixiu; Li, Xia; Xie, Tian; Brinkman, Kathryn L.; Teh, Bin S.; Butler, E. Brian; Xu, Bo; Zheng, Shu

doi:10.1016/j.ijrobp.2012.01.092

Cited by 17 publications

(7 citation statements)

References 17 publications

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“…Several classes of NFκB inhibitors are currently being tested in combination with RT including IKK inhibitors [33], inhibitory peptides [34], antisense RNA [35,36], proteasome inhibitors [37,38] and dietary agents that can block at various steps leading to NFκB activation and sensitize the tumor cells to the beneficial effects of radiation. Incidentally, radiosensitization of tumors have been reported with a number of plant polyphenols and an impressive number of clinical trials are currently ongoing to test the efficacy of drugs that could specifically inhibit NFκB ( www.clincaltrials.gov ).…”

Section: Discussionmentioning

confidence: 99%

Novel Synthetic Monoketone Transmute Radiation-Triggered NFκB-Dependent TNFα Cross-Signaling Feedback Maintained NFκB and Favors Neuroblastoma Regression

et al. 2013

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Recently, we demonstrated that radiation (IR) instigates the occurrence of a NFκB-TNFα feedback cycle which sustains persistent NFκB activation in neuroblastoma (NB) cells and favors survival advantage and clonal expansion. Further, we reported that curcumin targets IR-induced survival signaling and NFκB dependent hTERT mediated clonal expansion in human NB cells. Herein, we investigated the efficacy of a novel synthetic monoketone, EF24, a curcumin analog in inhibiting persistent NFκB activation by disrupting the IR-induced NFκB-TNFα-NFκB feedback signaling in NB and subsequent mitigation of survival advantage and clonal expansion. EF24 profoundly suppressed the IR-induced NFκB-DNA binding activity/promoter activation and, maintained the NFκB repression by deterring NFκB-dependent TNFα transactivation/intercellular secretion in genetically varied human NB (SH-SY5Y, IMR-32, SK–PN–DW, MC-IXC and SK–N-MC) cell types. Further, EF24 completely suppressed IR-induced NFκB-TNFα cross-signaling dependent transactivation/translation of pro-survival IAP1, IAP2 and Survivin and subsequent cell survival. In corroboration, EF24 treatment maximally blocked IR-induced NFκB dependent hTERT transactivation/promoter activation, telomerase activation and consequent clonal expansion. EF24 displayed significant regulation of IR-induced feedback dependent NFκB and NFκB mediated survival signaling and complete regression of NB xenograft. Together, the results demonstrate for the first time that, novel synthetic monoketone EF24 potentiates radiotherapy and mitigates NB progression by selectively targeting IR-triggered NFκB-dependent TNFα-NFκB cross-signaling maintained NFκB mediated survival advantage and clonal expansion.

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Section: Discussionmentioning

confidence: 99%

Novel Synthetic Monoketone Transmute Radiation-Triggered NFκB-Dependent TNFα Cross-Signaling Feedback Maintained NFκB and Favors Neuroblastoma Regression

et al. 2013

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“…Also, ATM is activated following the inhibition of PARP and may function in the upstream of HR in order to repair certain types of DSB [109]. Besides PARP-1, adopting other inhibitors to target major components of the DDR, such as ATM, ATR, DNA-PK, Chk1 and Chk2, can also confer radio- and/or chemosensitivity in cancer cells [110]. …”

Section: Mirna and The Downstream Effector Genes Of Radiation Relamentioning

confidence: 99%

MicroRNA and signal transduction pathways in tumor radiation response

Zhao

Cao

2013

Cellular Signalling

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Tumor radiation response is an essential issue in radiotherapy and a core determining factor of tumor radioresistance or radiosensitivity. Multiple factors can influence tumor radiation response, and among them tumor genetic and epigenetic background, tumor microenvironment and tumor blood flow status may take a leading role. During the whole process of tumor radiation response, tumor radiosensitivity can be regulated in an orderly manner through some classical signal transduction pathways. Although these pathways have already owned multiple biological functions and involved in the process of carcinogenesis, their regulatory roles in tumor radiation response can not be ignored. MicroRNA (miRNA) is a class of non-coding RNA of about 22 nucleotides in length, which binds to the 3’-untranslated region (3’-UTR) of target gene and controls the expression of it at the post-transcriptional level. MiRNA participates in numerous physiology and pathology processes and acts as oncogene or tumor suppressor to affect cancer progression. Through interplaying with the key components in radiation related signal transduction pathways, miRNA could effectively activate the expression of DNA damage response genes and cell cycle related genes in nucleus, and play a critical role in the modulation of radiation response and radiosensitivity in tumor cells. In this review, we mainly elucidate the regulatory mechanisms and functions of miRNA in these radiation related signal transduction pathways from three different aspects which include the upstream receptors, midstream transducer pathways, and downstream effector genes.

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“…However, in the A549 cells the level of γ-H2AX began to decrease 4 h after irradiation ( Figure 4E ). DNA-PKs are key proteins in the nonhomologous end-joining (NHEJ) repair mechanism 13 . In the RT+HS group for the H1975 cells and A549 cells, the expression of the DNA-PKcs was detected and it was found to be significantly enhanced as compared to the RT group.…”

Section: Resultsmentioning

confidence: 99%

EGFR tyrosine kinase inhibitor HS-10182 increases radiation sensitivity in non-small cell lung cancers with EGFR T790M mutation

Chen

Wang

Zhao

et al. 2018

Cancer Biology & Medicine

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Objective:To investigate the potential of HS-10182, a second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), as a radiosensitizer in non-small cell lung cancer (NSCLC).Methods:Two cell lines of NSCLCs, A549 that possesses wild-type (WT) EGFRs and H1975 that possesses EGFR L858R/T790M double mutations, were treated with HS-10182 at various concentrations, and cell viabilities were determined using the MTS assay. The cells were tested by clonogenic survival assays to identify the radiosensitivity of both groups. Western blot was performed to analyze the expression of phosphorylated EGFR, AKT, DNA-dependent protein kinase, and catalytic subunit (DNA-PKcs) proteins. Immunofluorescence analyses were performed to examine the formation and changes in nuclear γ-H2AX foci. Cell apoptosis was examined by flow cytometry and Western blots for cleaved caspase-3, -8, -9, and cleaved poly ADP-ribose polymerase (PARP). Furthermore, we established xenograft models in mice and the effects of different treatments on tumor growth were then assessed.Results:Clonogenic survival assays revealed that HS-10182 significantly enhanced the radiosensitivity of H1975 cells but not A549 cells [dose enhancement ratios (DERs)=2.36 (P < 0.05) vs. 1.43 (P > 0.05)]. Western blot results showed that HS-10182 increased the levels of cleaved caspase-3, -8, -9, and cleaved PARP in H1975 cells but not in A549 cells. In addition, flow cytometry analysis showed that HS-10182 enhanced irradiation-induced apoptosis in H1975. Immunofluorescence results found that HS-10182 increased the average number of γ-H2AX foci after irradiation in H1975 cells, but not in A549 cells. Combined radiation and HS-10182 treatment increased the expression of DNA-PKcs but this increase was more significant in H1975 cells than in A549 cells. Moreover, HS-10182 suppressed the increased expression of Rad50 in H1975 cells in response to irradiation. In vivo experiments found that the combined therapy significantly inhibited tumor growth. Conclusions:HS-10182 enhances the radiosensitivity of H1975 cells which is possibly because that HS-10182 could enhance irradiation-induced apoptosis, increase irradiation-induced DNA damage, and cause a delay in DNA damage repair. Our findings suggest that radiotherapy combined HS-10182 is a novel treatment for lung cancer cells which have acquired the T790M mutation. HS-10182 could be brought to the clinic as a radiosensitizer in NSCLCs with the EGFR T790M mutation.

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Identification and Characterization of a Small Inhibitory Peptide That Can Target DNA-PKcs Autophosphorylation and Increase Tumor Radiosensitivity

Cited by 17 publications

References 17 publications

Novel Synthetic Monoketone Transmute Radiation-Triggered NFκB-Dependent TNFα Cross-Signaling Feedback Maintained NFκB and Favors Neuroblastoma Regression

Novel Synthetic Monoketone Transmute Radiation-Triggered NFκB-Dependent TNFα Cross-Signaling Feedback Maintained NFκB and Favors Neuroblastoma Regression

MicroRNA and signal transduction pathways in tumor radiation response

EGFR tyrosine kinase inhibitor HS-10182 increases radiation sensitivity in non-small cell lung cancers with EGFR T790M mutation

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