The CGL1 (HeLa × Normal Skin Fibroblast) Human Hybrid Cell Line: A History of Ionizing Radiation Induced Effects on Neoplastic Transformation and Novel Future Directions in SNOLAB

Pirkkanen, Jake; Boreham, Douglas R.; Mendonca, Marc S.

doi:10.1667/rr14911.1

Cited by 12 publications

(17 citation statements)

References 116 publications

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“…cern.ch/event/436589/). The increasing interest in this field and the establishment of new projects, such as the REPAIR Project at SNOLAB (36,37), will have a significant effect on both basic knowledge and applied research.…”

Section: Deep Underground Laboratories Around the World: The Most Effmentioning

confidence: 99%

Fruit Flies Provide New Insights in Low-Radiation Background Biology at the INFN Underground Gran Sasso National Laboratory (LNGS)

et al. 2018

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Deep underground laboratories (DULs) were originally created to host particle, astroparticle or nuclear physics experiments requiring a low-background environment with vastly reduced levels of cosmic-ray particle interference. More recently, the range of science projects requiring an underground experiment site has greatly expanded, thus leading to the recognition of DULs as truly multidisciplinary science sites that host important studies in several fields, including geology, geophysics, climate and environmental sciences, technology/instrumentation development and biology. So far, underground biology experiments are ongoing or planned in a few of the currently operating DULs. Among these DULs is the Gran Sasso National Laboratory (LNGS), where the majority of radiobiological data have been collected. Here we provide a summary of the current scenario of DULs around the world, as well as the specific features of the LNGS and a summary of the results we obtained so far, together with other findings collected in different underground laboratories. In particular, we focus on the recent results from our studies of Drosophila melanogaster, which provide the first evidence of the influence of the radiation environment on life span, fertility and response to genotoxic stress at the organism level. Given the increasing interest in this field and the establishment of new projects, it is possible that in the near future more DULs will serve as sites of radiobiology experiments, thus providing further relevant biological information at extremely low-dose-rate radiation. Underground experiments can be nicely complemented with above-ground studies at increasing dose rate. A systematic study performed in different exposure scenarios provides a potential opportunity to address important radiation protection questions, such as the dose/dose-rate relationship for cancer and non-cancer risk, the possible existence of dose/dose-rate threshold(s) for different biological systems and/or end points and the possible role of radiation quality in triggering the biological response.

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Section: Deep Underground Laboratories Around the World: The Most Effmentioning

confidence: 99%

Fruit Flies Provide New Insights in Low-Radiation Background Biology at the INFN Underground Gran Sasso National Laboratory (LNGS)

et al. 2018

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“…To our knowledge, this is the first study to report frequencies of IR-induced normal cell transformation in vitro following HDACi pretreatment. Cellular transformation assays assessing anchorage-independent growth in soft agar of irradiated primary human fibroblasts or CGL1 HeLa/fibroblast hybrid cells ( 72 ) have been employed in radiobiology for decades as a surrogate in vitro model capable of recapitulating some of the essential features of in vivo human carcinogenesis ( 73 ). The frequencies of NFF28 fibroblast transformation following cesium-137 γ-rays, 200 MeV protons, 290 MeV/n C-12 ions, and 350 MeV/n O-16 ions we measured in this study ( Figures 10 , 11 ) are similar to those reported previously by the Sutherland group for low-passage NFF28 fibroblasts exposed to other proton energies, 250 kVp X-rays and intermediate to high LET Si-28, Ti-48, and Fe-56 ions ( 45 – 48 ).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Histone Deacetylase Inhibitors as Radiosensitizers for Proton and Light Ion Radiotherapy

et al. 2021

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Significant opportunities remain for pharmacologically enhancing the clinical effectiveness of proton and carbon ion-based radiotherapies to achieve both tumor cell radiosensitization and normal tissue radioprotection. We investigated whether pretreatment with the hydroxamate-based histone deacetylase inhibitors (HDACi) SAHA (vorinostat), M344, and PTACH impacts radiation-induced DNA double-strand break (DSB) induction and repair, cell killing, and transformation (acquisition of anchorage-independent growth in soft agar) in human normal and tumor cell lines following gamma ray and light ion irradiation. Treatment of normal NFF28 primary fibroblasts and U2OS osteosarcoma, A549 lung carcinoma, and U87MG glioma cells with 5–10 µM HDACi concentrations 18 h prior to cesium-137 gamma irradiation resulted in radiosensitization measured by clonogenic survival assays and increased levels of colocalized gamma-H2AX/53BP1 foci induction. We similarly tested these HDACi following irradiation with 200 MeV protons, 290 MeV/n carbon ions, and 350 MeV/n oxygen ions delivered in the Bragg plateau region. Unlike uniform gamma ray radiosensitization, effects of HDACi pretreatment were unexpectedly cell type and ion species-dependent with C-12 and O-16 ion irradiations showing enhanced G0/G1-phase fibroblast survival (radioprotection) and in some cases reduced or absent tumor cell radiosensitization. DSB-associated foci levels were similar for proton-irradiated DMSO control and SAHA-treated fibroblast cultures, while lower levels of induced foci were observed in SAHA-pretreated C-12 ion-irradiated fibroblasts. Fibroblast transformation frequencies measured for all radiation types were generally LET-dependent and lowest following proton irradiation; however, both gamma and proton exposures showed hyperlinear transformation induction at low doses (≤25 cGy). HDACi pretreatments led to overall lower transformation frequencies at low doses for all radiation types except O-16 ions but generally led to higher transformation frequencies at higher doses (>50 cGy). The results of these in vitro studies cast doubt on the clinical efficacy of using HDACi as radiosensitizers for light ion-based hadron radiotherapy given the mixed results on their radiosensitization effectiveness and related possibility of increased second cancer induction.

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“…The long-term research goals of the REPAIR project are focused on understanding the effects of a deep-underground environment in a variety of biological model systems (Pirkkanen et al, 2017;Thome et al, 2017c). Lake whitefish embryogenesis was chosen as a model system in this pilot project in order to evaluate the viability of performing biological experiments deep-underground within SNOLAB, where REPAIR is located.…”

Section: Discussionmentioning

confidence: 99%

“…Researching the Effects of the Presence and Absence of Ionizing Radiation (REPAIR) is a recently established research project within SNOLAB. The goal of this project is to study the effects of exposure to a deep underground environment shielded from naturally occurring background radiation on biological systems, including whole organism models (Pirkkanen et al, 2017;Thome et al, 2017c). One of the whole organism models that REPAIR is utilizing is the embryonic development of lake whitefish (Coregonus clupeaformis).…”

Section: Introductionmentioning

confidence: 99%

A Research Environment 2 km Deep-Underground Impacts Embryonic Development in Lake Whitefish (Coregonus clupeaformis)

et al. 2020

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Biological research conducted in deep-underground environments is limited due to the lack of scientific infrastructure to accommodate the investigations, and only a few studies have utilized complex whole organism models. In this study, lake whitefish (Coregonus clupeaformis) embryogenesis was examined in two different unique laboratory environments; at the Earth's surface and 2 km deep underground shielded from cosmic radiation. Established developmental endpoints and morphometric analysis were utilized to investigate differences between lake whitefish embryos reared in these two laboratories. No significant differences were observed between the surface and underground laboratories with respect to the timing of hatch or percent survival. However, a significant increase in body length and body weight of up to 10% was observed in embryos reared underground. These findings have been interpreted and discussed in the context of the novel research challenges faced in an inherently difficult to control deep-underground environment. This study represents one of the few investigations with an established whole organism model deep-underground and provides an opportunity to discuss the highly unique technical and logistical challenges of conducting biological experiments in this novel field of scientific research.

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The CGL1 (HeLa × Normal Skin Fibroblast) Human Hybrid Cell Line: A History of Ionizing Radiation Induced Effects on Neoplastic Transformation and Novel Future Directions in SNOLAB

Cited by 12 publications

References 116 publications

Fruit Flies Provide New Insights in Low-Radiation Background Biology at the INFN Underground Gran Sasso National Laboratory (LNGS)

Fruit Flies Provide New Insights in Low-Radiation Background Biology at the INFN Underground Gran Sasso National Laboratory (LNGS)

Evaluation of Histone Deacetylase Inhibitors as Radiosensitizers for Proton and Light Ion Radiotherapy

A Research Environment 2 km Deep-Underground Impacts Embryonic Development in Lake Whitefish (Coregonus clupeaformis)

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