Hyperthermia adds to trabectedin effectiveness and thermal enhancement is associated with BRCA2 degradation and impairment of DNA homologous recombination repair
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
26933761
DOI
10.1002/ijc.30070
Knihovny.cz E-resources
- Keywords
- DNA repair, hyperthermia, sarcoma, trabectedin,
- MeSH
- Antineoplastic Agents, Alkylating pharmacology MeSH
- Apoptosis drug effects radiation effects MeSH
- Models, Biological MeSH
- Drug Resistance, Neoplasm radiation effects MeSH
- Dioxoles pharmacology MeSH
- Histones metabolism MeSH
- Hyperthermia, Induced * MeSH
- Caspases metabolism MeSH
- Cell Cycle Checkpoints drug effects radiation effects MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- BRCA2 Protein metabolism MeSH
- Proteolysis drug effects radiation effects MeSH
- Recombinational DNA Repair drug effects radiation effects MeSH
- Rad51 Recombinase metabolism MeSH
- Sarcoma metabolism pathology therapy MeSH
- Tetrahydroisoquinolines pharmacology MeSH
- Trabectedin MeSH
- Protein Transport MeSH
- Protein Binding MeSH
- Cell Survival drug effects radiation effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antineoplastic Agents, Alkylating MeSH
- Dioxoles MeSH
- Histones MeSH
- Caspases MeSH
- BRCA2 Protein MeSH
- Rad51 Recombinase MeSH
- Tetrahydroisoquinolines MeSH
- Trabectedin MeSH
The tetrahydroisoquinoline trabectedin is a marine compound with approved activity against human soft-tissue sarcoma. It exerts antiproliferative activity mainly by specific binding to the DNA and inducing DNA double-strand breaks (DSB). As homologous recombination repair (HRR)-deficient tumors are more susceptible to trabectedin, hyperthermia-mediated on-demand induction of HRR deficiency represents a novel and promising strategy to boost trabectedin treatment. For the first time, we demonstrate enhancement of trabectedin effectiveness in human sarcoma cell lines by heat and characterize cellular events and molecular mechanisms related to heat-induced effects. Hyperthermic temperatures (41.8 or 43°C) enhanced significantly trabectedin-related clonogenic cell death and G2/M cell cycle arrest followed by cell type-dependent induction of apoptosis or senescence. Heat combination increased accumulation of γH2AX foci as key marker of DSBs. Expression of BRCA2 protein, an integral protein of the HRR machinery, was significantly decreased by heat. Consequently, recruitment of downstream RAD51 to γH2AX-positive repair foci was almost abolished indicating relevant impairment of HRR by heat. Accordingly, enhancement of trabectedin effectiveness was significantly augmented in BRCA2-proficient cells by hyperthermia and alleviated in BRCA2 knockout or siRNA-transfected BRCA2 knockdown cells. In peripheral blood mononuclear cells isolated from sarcoma patients, increased numbers of nuclear γH2AX foci were detected after systemic treatment with trabectedin and hyperthermia of the tumor region. The findings establish BRCA2 degradation by heat as a key factor for a novel treatment strategy that allows targeted chemosensitization to trabectedin and other DNA damaging antitumor drugs by on-demand induction of HRR deficiency.
Department of Genetics Cancer Genomics Netherlands Erasmus Medical Center Rotterdam The Netherlands
Department of Internal Medicine Philipps University of Marburg Marburg Germany
Department of Medicine 2 University Hospital Grosshadern University of Munich Munich Germany
Department of Medicine 3 University Hospital Grosshadern University of Munich Munich Germany
Department of Radiation Oncology Erasmus Medical Center Rotterdam The Netherlands
Department of Radiation Oncology University Hospital Grosshadern University of Munich Munich Germany
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