Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth control

Golding, Sarah E.; Rosenberg, Elizabeth; Adams, Bret R.; Wignarajah, Shayalini; Beckta, Jason M.; O’Connor, Mark J.; Valerie, Kristoffer

doi:10.4161/cc.11.6.19576

Cited by 87 publications

(77 citation statements)

References 25 publications

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“…For example, the possibility of using ATM inhibitors in combination with radiotherapy for treatment of glioblastoma -which arise in the brain, a region of low proliferation -has already begun to be explored (19,20). An ATM inhibitor was also found to sensitize tumor xenografts to the DNA-damaging cancer therapeutic drugs etoposide and irinotecan, without any reported normal tissue toxicity (21).…”

Section: Role Of Proliferation In Sensitivity To Atm Lossmentioning

confidence: 99%

Radiation and ATM inhibition: the heart of the matter

Hammond¹,

Muschel²

2014

J. Clin. Invest.

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C o m m e n t a r y 3 2 8 9 jci.org Volume 124 Number 8 August 2014Radiation and ATM inhibition: the heart of the matter The role of ATM in damage responseThe ataxia telangiectasia mutated (ATM) kinase is a member of the PI3K-like protein kinase (PIKK) family with extensive roles in DNA damage response signaling (reviewed in ref. 1). In addition, ATM can respond to non-DNA-damaging stresses and has recently been described as having a role in neoangiogenesis in a melanoma model (2-5). DNA damage leads to activation of ATM kinase activity and thus phosphorylation of a myriad of downstream targets, including p53, CHK2, and KAP-1 (6, 7). This activation triggers cell cycle checkpoints, arrest, and delays in the G 1 , S, and G 2 phases of the cell cycle and enables DNA repair of double-stranded breaks both by homologous recombination and by nonhomologous end joining (8, 9). Hence, fibroblasts and tumor cells are radiosensitized to X-ray radiation therapy (XRT) in culture by pharmacological ATM inhibition, or by ATM mutation and deletion (10). These data suggest that inhibition of ATM should radiosensitize tumors; however, there is a hesitancy to employ this strategy clinically, due to fears that normal tissues could be substantially sensitized as well. This reluctance is well founded, as it is based on the catastrophic response of patients with ataxia telangiectasia (AT) to XRT. The AT syndrome, which is now characterized in part by extreme radiosensitivity, is caused by mutations in the ATM gene. Before AT was fully characterized, a few patients who developed lymphoma (a frequent event in AT) were radiated to treat mediastinal cancers and suffered drastic side effects. Those few reports stressed severe mucositis of the esophagus and skin desquamation (e.g., ref.11). This led to the subsequently proven supposition that ATM plays an important role in the response and repair of DNA damage, but also the understandable reticence of clinicians to consider XRT for AT patients and reluctance to use AT inhibitors because of the potential normal tissue sensitivity. While the clinical observations point to mucous membranes and skin as targets for deleterious normal tissue effects, it should be remembered that thoracic radiation also inevitably results in some radiation dose to the heart. Work over recent years has shown that irradiation of the heart during treatment for breast cancer leads to long-term increased risk for atherosclerotic coronary disease (12). However, this dose-dependent pathology evolves over the long term and is not replicated in mice unless they are also predisposed to atherosclerosis, as in mice with ApoE deficiency (13), and so might not emerge in some model systems. An elegant model to understand the role of ATMIn this issue, Moding et al. used an innovative and intricate system to distinguish the effects of ATM deletion in endothelium from the heart and from tumors (14). The authors used a sarcoma model that they previously established in mice with mutant Kras G12D and p53 flanked by inactivating stop ...

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Section: Role Of Proliferation In Sensitivity To Atm Lossmentioning

confidence: 99%

Radiation and ATM inhibition: the heart of the matter

Hammond¹,

Muschel²

2014

J. Clin. Invest.

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“…In general, cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% Cosmic calf serum, 100 units/ml of penicillin and 100 μg/ml of streptomycin at 37°C in 95% air/5% CO 2 [35][36][37][38][39].…”

Section: Cell Culturementioning

confidence: 99%

Folic Acid-Decorated Polyamidoamine Dendrimer Mediates Selective Uptake and High Expression of Genes in Head and Neck Cancer Cells

Kittrell

Yeudall

2016

Nanomedicine (Lond.)

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Aim: Folic acid (FA)-decorated polyamidoamine dendrimer G4 (G4-FA) was synthesized and studied for targeted delivery of genes to head and neck cancer cells expressing high levels of folate receptors (FRs). Methods: Cellular uptake, targeting specificity, cytocompatibility and transfection efficiency were evaluated. Results: G4-FA competes with free FA for the same binding site. G4-FA facilitates the cellular uptake of DNA plasmids in a FR-dependent manner and selectively delivers plasmids to FR-high cells, leading to enhanced gene expression. Conclusion: G4-FA is a suitable vector to deliver genes selectively to head and neck cancer cells. The fundamental understandings of G4-FA as a vector and its encouraging transfection results for head and neck cancer cells provided support for its further testing in vivo.

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“…Phosphorylated ATM regulates cell cycle checkpoints through p53 phosphorylation at Ser15 and activates checkpoint kinase 2 (CHK2) through phosphorylation at Thr68 (24,25). As ATM kinase is a potential therapeutic target for the therapy of GBM, the ATM inhibitor increases the death of GBM cells combined with radiation (9,26,27). Histone H2AX can be phosphorylated by p-ATM to γH2AX and takes parts in the repair of DNA damage directly, thus, we not only tested the level of p-ATM but also γH2AX to measure the DNA damage repair after radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

β-elemene enhances both radiosensitivity and chemosensitivity of glioblastoma cells through the inhibition of the ATM signaling pathway

et al. 2015

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Abstract. Glioblastoma multiforme (GBM), a tumor associated with poor prognosis, is known to be resistant to radiotherapy and alkylating agents such as temozolomide (TMZ). β-elemene, a monomer found in Chinese traditional herbs extracted from Curcuma wenyujin, is currently being used as an antitumor drug for different types of tumors including GBM. In the present study, we investigated the roles of β-elemene in the radiosensitivity and chemosensitivity of GBM cells. Human GBM cell lines U87-MG, T98G, U251, LN229 and rat C6 cells were treated with β-elemene combined with radiation or TMZ. We used MTT and colony forming assays to evaluate the proliferation and survival of the cells, and the comet assay to observe DNA damage. Expression of proteins was analyzed by immunoblotting. In the present study, we found that β-elemene inhibited the proliferation and survival of different GBM cell lines when combined with radiotherapy or TMZ via inhibition of DNA damage repair. Treatment of GBM cells with β-elemene decreased the phosphorylation of ataxia telangiectasia mutated (ATM), AKT and ERK following radiotherapy or chemotherapy. These results revealed that β-elemene could significantly increase the radiosensitivity and chemosensitivity of GBM. β-elemene may be used as a potential drug in combination with the radiotherapy and chemotherapy of GBM.

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Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth control

Cited by 87 publications

References 25 publications

Radiation and ATM inhibition: the heart of the matter

Radiation and ATM inhibition: the heart of the matter

Folic Acid-Decorated Polyamidoamine Dendrimer Mediates Selective Uptake and High Expression of Genes in Head and Neck Cancer Cells

β-elemene enhances both radiosensitivity and chemosensitivity of glioblastoma cells through the inhibition of the ATM signaling pathway

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