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

Sekhar, Konjeti R.; Sonar, Vijayakumar N.; Venkatraj, M.; Sasi, Soumya; Laszlo, Andrei; Sawani, Jamil; Horikoshi, Nobuo; Higashikubo, Ryuji; Bristow, Robert G.; Borrelli, Michael J.; Crooks, Peter A.; Lepock, James R.; Roti, Joseph L. Roti; Freeman, Michael L.

doi:10.1158/0008-5472.can-06-3212

Cited by 35 publications

(29 citation statements)

References 41 publications

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“…In a recent report, we have shown that a novel heat enhancer reduces the threshold for both heat radiosensitization and the heatinduced delay in 53BP1 complex formation (48). Thus, rapid assays using the heat-induced delay of 53BP1 complex formation as a readout could be used to screen for heat enhancers and heat mimics.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

Laszlo

Fleischer

2009

Cancer Research

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“…17,18), histone acetyltransferase depleting agents (19), and microtubule disruption agents (20). So, targeting cancer cells to undergo mitotic catastrophe is also considered to be a new efficacy strategy to overcome the drug or radiation resistances in cancer therapy (20,21).…”

Section: Introductionmentioning

confidence: 99%

Inactivation of DNA-Dependent Protein Kinase Leads to Spindle Disruption and Mitotic Catastrophe with Attenuated Checkpoint Protein 2 Phosphorylation in Response to DNA Damage

Shang

Huang

et al. 2010

Cancer Research

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DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is well known as a critical component involving the nonhomologous end joining pathway of DNA double-strand breaks repair. Here, we showed another important role of DNA-PKcs in stabilizing spindle formation and preventing mitotic catastrophe in response to DNA damage. Inactivation of DNA-PKcs by small interfering RNA or specific inhibitor NU7026 resulted in an increased outcome of polyploidy after 2-Gy or 4-Gy irradiation. Simultaneously, a high incidence of multinucleated cells and multipolar spindles was detected in DNA-PKcs-deficient cells. Time-lapse video microscopy revealed that depression of DNA-PKcs results in mitotic catastrophe associated with mitotic progression failure in response to DNA damage. Moreover, DNA-PKcs inhibition led to a prolonged G 2 -M arrest and increased the outcome of aberrant spindles and mitotic catastrophe in Ataxia-telangiectasia mutated kinase (ATM)-deficient AT5BIVA cells. We have also revealed the localizations of phosphorylated DNA-PKcs/T2609 at the centrosomes, kinetochores, and midbody during mitosis. We have found that the association of DNA-PKcs and checkpoint kinase 2 (Chk2) is driven by Ku70/80 heterodimer. Inactivation of DNA-PKcs strikingly attenuated the ionizing radiation-induced phosphorylation of Chk2/T68 in both ATMefficient and ATM-deficient cells. Chk2/p-T68 was also shown to localize at the centrosomes and midbody. These results reveal an important role of DNA-PKcs on stabilizing spindle formation and preventing mitotic catastrophe in response to DNA damage and provide another prospect for understanding the mechanism coupling DNA repair and the regulation of mitotic progression. Cancer Res; 70(9); 3657-66. ©2010 AACR.

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“…α-tubulin expression was analyzed in all the experiments as internal control. radiosensitization, 25,26) and inhibitors of matrix metalloproteinase 3 (MMP-3) enhanced heat shock-induced cell death in HeLa cells. 27) In contrast to these compounds, 5-ALA is a natural amino acid with no toxic side effects on normal cells.…”

Section: Discussionmentioning

confidence: 99%

5-aminolevulinic acid enhances cell death under thermal stress in certain cancer cell lines

Chibazakura

Toriyabe

Fujii

et al. 2015

Bioscience, Biotechnology, and Biochemistry

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5-aminolevulinic acid (5-ALA) is contained in all organisms and a starting substrate for heme biosynthesis. Since administration of 5-ALA specifically leads cancer cells to accumulate protoporphyrin IX (PpIX), a potent photosensitizer, we tested if 5-ALA also serves as a thermosensitizer. 5-ALA enhanced heat-induced cell death of cancer cell lines such as HepG2, Caco-2, and Kato III, but not other cancer cell lines including U2-OS and normal cell lines including WI-38. Those 5-ALA-sensitive cancer cells, but neither U2-OS nor WI-38, accumulated intracellular PpIX and exhibited an increased reactive oxygen species (ROS) generation under thermal stress with 5-ALA treatment. In addition, blocking the PpIX-exporting transporter ABCG2 in U2-OS and WI-38 cells enhanced their cell death under thermal stress with 5-ALA. Finally, a ROS scavenger compromised the cell death enhancement by 5-ALA. These suggest that 5-ALA can sensitize certain cancer cells, but not normal cells, to thermal stress via accumulation of PpIX and increase of ROS generation.

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

Cited by 35 publications

References 41 publications

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

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

Inactivation of DNA-Dependent Protein Kinase Leads to Spindle Disruption and Mitotic Catastrophe with Attenuated Checkpoint Protein 2 Phosphorylation in Response to DNA Damage

5-aminolevulinic acid enhances cell death under thermal stress in certain cancer cell lines

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