Alterations in heat-induced radiosensitization accompanied by nuclear structure alterations in Chinese hamster cells

Laszlo, Andrei; Davidson, Teri; Harvey, Amanda; Sim, Julia; Malyapa, Robert S.; Spitz, Douglas R.; Roti, Joseph L. Roti

doi:10.1080/02656730500394296

Cited by 14 publications

(11 citation statements)

References 49 publications

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“…Thermalmediated destabilization of protein conformation represents a common underlying biophysical mechanism for hyperthermicinduced cell killing and thermal radiosensitization (2,7,16,17). Protein destabilization and unfolding also initiates the acquisition of Hsf1 DNA-binding activity (18).…”

Section: Resultsmentioning

confidence: 99%

“…The foremost molecular event governing thermal radiosensitization is the unfolding and aggregation of a subset of cellular proteins (2). Heat shock-mediated alterations of the biophysical properties of irradiated chromatin, temperature-dependent inhibition of DNA double-strand break ligation (1), and the usurping of signal transduction pathways are mainly a consequence of protein unfolding and aggregation (7). Thus, thermal destabilization of protein conformation represents an underlying biophysical process that can be exploited.…”

Section: Introductionmentioning

confidence: 99%

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Novel Chemical Enhancers of Heat Shock Increase Thermal Radiosensitization through a Mitotic Catastrophe Pathway

et al. 2007

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Radiation therapy combined with adjuvant hyperthermia has the potential to provide outstanding local-regional control for refractory disease. However, achieving therapeutic thermal dose can be problematic. In the current investigation, we used a chemistry-driven approach with the goal of designing and synthesizing novel small molecules that could function as thermal radiosensitizers..2]octan-3-ol was identified as a compound that could lower the threshold for Hsf1 activation and thermal sensitivity. Enhanced thermal sensitivity was associated with significant thermal radiosensitization. We established the structural requirements for activity: the presence of an N-benzenesulfonylindole or N-benzylindole moiety linked at the indolic 3-position to a 2-(1-azabicyclo[2.2.2]octan-3-ol) or 2-(1-azabicyclo[2.2.2]octan-3-one) moiety. These small molecules functioned by exploiting the underlying biophysical events responsible for thermal sensitization. Thermal radiosensitization was characterized biochemically and found to include loss of mitochondrial membrane potential, followed by mitotic catastrophe. These studies identified a novel series of small molecules that represent a promising tool for the treatment of recurrent tumors by ionizing radiation. [Cancer Res 2007;67(2):695-701]

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel Chemical Enhancers of Heat Shock Increase Thermal Radiosensitization through a Mitotic Catastrophe Pathway

et al. 2007

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“…The ability of the molecular chaperone Hsc70 to modulate the heat-induced delay in 53BP1 complex formation is intriguing. The delay is modulated in both heat radiosensitization-resistant cells (16) Fig. 4C).…”

Section: Discussionmentioning

confidence: 99%

“…Clonogenic survival curves were generated as described (16). We did not find any trypsin effects for radiation or the combination of heat and irradiation (16).…”

Section: Methodsmentioning

confidence: 99%

“…Confluent or serum-starved cells were used throughout these studies to avoid cell cycle effects. Parental wildtype HA-1 and heat radiosensitization-resistant HR-1 cells were grown as described (16). MCF7, HeLa cells, HEK293, and 53BP À/À and 53BP1 +/+ MEFs were grown in DME containing 10% FCS and antibiotics, with the addition of pyruvate and h-mercaptoethanol for the growth of the MEFs (15).…”

Section: Methodsmentioning

confidence: 99%

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Heat-Induced Perturbations of DNA Damage Signaling Pathways are Modulated by Molecular Chaperones

Laszlo

Fleischer

2009

Cancer Research

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Heat is one of the most potent radiosensitizers known. Several randomized trials have shown that hyperthermia is a good adjuvant for radiotherapy at several different cancer sites. However, the mechanism(s) involved in the interaction of heat and radiation that lead to radiosensitization remain to be elucidated. In this report, we have determined that heat induces perturbations in some of the earliest events in the cellular response to DNA damage induced by ionizing radiation. We studied the effect of heat on the formation of complexes containing ;-H2AX/MDC1/53BP1 in heated-irradiated cells. We found that the formation of this complex was delayed in heated-irradiated cells, in a heat but not radiation dose-dependent manner. The length of the heat-induced delay of complex formation was attenuated in thermotolerant and heat radiosensitization-resistant cells. The length of the delay of ;-H2AX/MDC1/53BP1 complex formation correlated with the magnitude of heat radiosensitization and was modulated by the molecular chaperone Hsc70. Heat radiosensitization was attenuated in 53BP1-null cells, implying that the delay of the formation of the ;-H2AX/MDC1/53BP1 complex plays a role in heat radiosensitization. Heat also induced a delay of events in the DNA damage response that are downstream from 53BP1. Our results support the notion that heat-induced perturbations in the earliest events of the cellular response to ionizing radiation-induced DNA damage play a role in heat radiosensitization. [Cancer Res 2009;69(5):2042-9]

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Hyperthermia alters the interaction of proteins of the Mre11 complex in irradiated cells

2010

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Radiosensitization of mammalian cells by heat is believed to involve the inhibition of repair of DNA double-strand breaks (DSBs). The Mre11 complex (composed of Mre11, Rad50, and Nbs1) is involved in DSB repair and forms foci at sites of radiation-induced DSBs. Heat induces the translocation of a significant amount of Mre11, Rad50, and Nbs1 from the nucleus to the cytoplasm, but little is known about how heat affects the integrity of the proteins still remaining in nuclei, or alters kinetics of formation/disappearance of DNA repair foci in heated, irradiated cells. Here, we show that hyperthermia alters the interaction between proteins of the Mre11 complex in irradiated human melanoma cells and inhibits the formation of repair foci. At various times after X-irradiation and/or heating (2 h at 41.5 or 42.58C), the cells were fixed and stained for Mre11, Rad50, and Nbs1. Colocalization of proteins and formation and disappearance of nuclear foci in heated and/or irradiated cells, determined using confocal microscopy, were compared. In heated, irradiated cells, focus formation was inhibited for 2-8 h, and colocalization of the proteins of the Mre11 complex was reduced for 12-24 h post-treatment. Colocalization was recovered in irradiated cells within 24 h after heating at 41.58C, but was inhibited longer after heating at 42.58C. The decreased colocalization in heated, irradiated cells suggests that there is a decrease in protein interaction, and Mre11 complexes in nuclei disassemble after heating. Such changes could be involved, at least in part, in heat radiosensitization and inhibition of DSB repair. Also, the kinetics of disassembly and reassembly of Mre11 complexes appears to be dependent upon treatment temperature. ' 2010International Society for Advancement of Cytometry

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Alterations in heat-induced radiosensitization accompanied by nuclear structure alterations in Chinese hamster cells

Cited by 14 publications

References 49 publications

Novel Chemical Enhancers of Heat Shock Increase Thermal Radiosensitization through a Mitotic Catastrophe Pathway

Novel Chemical Enhancers of Heat Shock Increase Thermal Radiosensitization through a Mitotic Catastrophe Pathway

Heat-Induced Perturbations of DNA Damage Signaling Pathways are Modulated by Molecular Chaperones

Hyperthermia alters the interaction of proteins of the Mre11 complex in irradiated cells

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