The response of human glioma cell lines to low-dose radiation exposure

Short, Susan C; Mitchell, Stephen; Boulton, P. S.; Woodcock, M.; Joiner, Michael C.

doi:10.1080/095530099139214

Cited by 69 publications

(18 citation statements)

References 18 publications

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“…The rationale for introducing these compounds into breast cancer treatment regimens is based on studies reporting overexpression of Notch receptors in breast cancers [3,19,25] and a central role for the Notch signaling pathway in the self-renewal process of breast cancer stem cells [6]. Furthermore, preclinical use of γ-secretase inhibitors reduced the number of breast cancer stem cells [20,24,25] and partially prevented radiation-induced reprogramming of non-tumorigenic breast cancer cells into breast cancer stem cells [16]. …”

Section: Discussionmentioning

confidence: 99%

“…Mouse studies suggest that Notch receptor and ligand expression and Notch activation are highly dynamic [25] and part of the general cellular response to oxidative stress [21,24]. Therefore, knowledge of the exact temporal expression pattern of the Notch receptor and ligand family members appears to be crucial for the design of effective treatment schedules.…”

Section: Discussionmentioning

confidence: 99%

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Radiation-Induced Notch Signaling in Breast Cancer Stem Cells

Lagadec

Vlashi

Alhiyari

et al. 2013

International Journal of Radiation Oncology*Biology*Physics

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Purpose Breast cancers are thought to be organized hierarchically with a small number of breast cancer stem cells able to self-renew and to regrow the entire tumor. Importantly, breast cancer stem cells are resistant to established chemotherapeutic agents and relatively resistant to radiation. Self-renewal of breast cancer stem cells is under control of the Notch signaling pathway, which suggests that targeting this pathway could be a novel way of eliminating breast cancer stem cells. The γ-secretase complex controls the final intramembranous cleavage step that activates Notch receptors upon binding of its ligands and specific inhibitors of γ-secretase, which prevent Notch activation, are currently clinically tested against solid cancers in combination with radiotherapy. Radiation activates Notch signaling and therefore, we sought to explore patterns of Notch receptor and ligand expression in response to radiation that could be crucial in defining optimal dosing schemes for γ-secretase inhibitors if combined with radiation. Methods and Materials Using MCF-7 and T47D breast cancer cell lines we used realtime RT-PCR to study the Notch pathway in response to radiation. Results We show that Notch receptor and ligand expression during the first 48 hours after irradiation followed a complex radiation dose-dependent pattern and was most pronounced in mammospheres, enriched for breast cancer stem cells. Additionally, radiation activated the Notch pathway. Treatment with a γ-secretase inhibitor prevented radiation-induced Notch family gene expression and led to a significant reduction in the size of the breast cancer stem cell pool. Conclusions Our results indicate that, if combined with radiation, γ-secretase inhibitors may prevent up-regulation of Notch receptor and ligand family members and thus reduce the number of surviving breast cancer stem cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Radiation-Induced Notch Signaling in Breast Cancer Stem Cells

Lagadec

Vlashi

Alhiyari

et al. 2013

International Journal of Radiation Oncology*Biology*Physics

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“…For this reason, Short et al . investigated the affect of low-dose irradiation on five human GBM cell lines (T98G, A7, U87MG, U138, and HGL21) and one anaplastic astrocytoma-derived cell line (U373) [15,16]. Survival time was calculated using the DMIPS method for T98G, A7, and U373, whereas the FC method (as modified by Wouters et al .)…”

Section: Experimental Studiesmentioning

confidence: 99%

“…Survival time was calculated using the DMIPS method for T98G, A7, and U373, whereas the FC method (as modified by Wouters et al .) was utilized for U87MG, U138, and HGL21 [15,16]. The authors were able to demonstrate the HRS phenomenon in all five GBM cell lines, with the most dramatic results obtained for the A7, U138, and TG98G lines.…”

Section: Experimental Studiesmentioning

confidence: 99%

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Three-Times Daily Ultrafractionated Radiation Therapy, A Novel and Promising Regimen for Glioblastoma Patients

Beauchesne

2013

Cancers

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Glioblastomas are considered to be one of the most radio resistant tumors. Despite new therapies, the prognosis of this disease remains dismal. Also, the mechanisms of radiation resistance in mammalian cells are more complex than once believed. Experimental studies have indicated that some human cell lines are sensitive to low radiation doses of <1 Gy. This phenomenon has been termed low-dose hyper-radio-sensitivity (HRS), and is more apparent in radio resistant cell lines, such as glioblastoma cells. Sensitivity may result from the inability of low dose radiation to efficiently induce repair mechanisms, whereas higher doses cause enough damage to trigger repair responses for radio resistance. In vitro studies have demonstrated this phenomenon using various human malignant glioma cell lines: (1) daily repeated irradiation of cells with low doses compared to irradiation using a single biologically equivalent dose resulted in significantly higher cell killing; (2) experiments conducted on glioma xenografts demonstrated that repeated irradiation with low doses was more effective for inhibiting tumor growth than a single dose. In order to confirm and validate these promising studies on HRS, a few phase II trials were developed. For translating the experimental observations into the clinic, ultra fractionation protocols (with three daily doses) were tested in glioblastoma patients. Tolerance and toxicity were the primary endpoints, with overall survival as a secondary endpoint. These protocols were initiated before concomitant radio chemotherapy became the standard of care. For these trials, patients with an unfavorable clinical prognostic factor of newly unresectable GBM were included. When comparing the results of these trials with international literature using multivariate analysis for both progression free survival and overall survival, ultra fractionated irradiation showed superiority over radiotherapy alone. In addition, it was found to be equivalent to treatment using radiotherapy and temozolomide. Therefore, ultra fractionated protocols may prolong survival of glioblastoma patients. In this review, we describe the main experimental data regarding low-dose hypersensitivity as well as the findings of clinical trials that have investigated this new radiotherapy regimen.

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Human malignant glioma cell lines are sensitive to low radiation doses

Beauchesne

Bertrand

et al. 2003

Intl Journal of Cancer

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Malignant gliomas display aggressive local behavior and are not cured by existing therapy. Some cell lines that are considered radioresistant respond to low radiation doses (<1 Gy) with increased cell killing (low-dose hypersensitivity). In our study, 4 of 5 human glioma cell lines exhibited significant X-ray sensitivity at doses below 1 Gy. The surviving fractions (SFs) obtained at 0.7 and/or 0.8 Gy were comparable to those at 1.5 Gy. Low-dose hypersensitivity was evident when irradiation was combined with etoposide treatment. Repeated irradiation with low doses was markedly more effective than irradiation with single, biologically equivalent doses in decreasing SFs, inhibiting xenograft tumor growth in mice. All experiments were conducted with an accelerator used in clinics, establishing that low-dose hypersensitivity was present following megavoltage X-irradiation. Malignant glioma is one of the most radioresistant tumor types and accounts for approximately 60% of all primary brain tumors in adults. The prognosis of malignant glioma patients remains dismal. The standard of care has been essentially unchanged for many decades: surgical resection of as much of the tumor as is safe, followed by radiation therapy and chemotherapy. Even under the best of circumstances, in which essentially all of the tumor seen on magnetic resonance imaging scan can be surgically removed and the patients fully treated with radiation and chemotherapy, mean survival is extended only from 2-3 months to 1 year. [1][2][3] Despite the widespread use of radiation therapy for the treatment of malignant glioma, the uniformly poor response of these tumors remains a critical problem in the management of these patients. 3 Disruption of cell-cycle arrest or apoptotic pathways by INK4a loss or by p53 mutations or inactivation (approx. 40 -60% of malignant gliomas have p53 mutations) associated with CDK4 amplification or Rb loss may be significant factors in determining the response of these tumors to irradiation and treatment outcome. 4 -6 The radiation survival response of mammalian cells is more complicated than once believed. A few studies indicate that some human cell lines are sensitive to killing by low radiation doses (Ͻ1 Gy). This has been termed low-dose hyper-radiosensitivity (HRS). [7][8][9][10][11] This may reflect differential triggering or induction of repair mechanisms. Cells may be sensitive to low doses because repair mechanisms are not induced, whereas higher doses may cause enough damage to induce or trigger repair mechanisms and, therefore, exhibit increased radioresistance. 9 We report here that 4 malignant glioma cell lines displayed a significant increase in X-ray radiosensitivity at doses below 1 Gy compared to the prediction extrapolated from a linear-quadratic (LQ) model that fits to the data at higher doses. In addition, this phenomenon was extended to 4 human melanoma cell lines and MRC5 human fibroblasts. Moreover, ultrafractionated irradiation with low doses was markedly more effective than conventional irradiati...

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The response of human glioma cell lines to low-dose radiation exposure

Abstract: Low-dose hypersensitivity is common in radioresistant glioma cell lines. This may have implications for the treatment of these tumours if further studies confirm that HRS translates to increased effectiveness per gray in vivo when very low doses per fraction are used.

Cited by 69 publications

References 18 publications

Radiation-Induced Notch Signaling in Breast Cancer Stem Cells

Radiation-Induced Notch Signaling in Breast Cancer Stem Cells

Three-Times Daily Ultrafractionated Radiation Therapy, A Novel and Promising Regimen for Glioblastoma Patients

Human malignant glioma cell lines are sensitive to low radiation doses

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