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.
- Klíčová slova
- DNA repair, hyperthermia, sarcoma, trabectedin,
- MeSH
- alkylační protinádorové látky farmakologie MeSH
- apoptóza účinky léků účinky záření MeSH
- biologické modely MeSH
- chemorezistence účinky záření MeSH
- dioxoly farmakologie MeSH
- histony metabolismus MeSH
- indukovaná hypertermie * MeSH
- kaspasy metabolismus MeSH
- kontrolní body buněčného cyklu účinky léků účinky záření MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- protein BRCA2 metabolismus MeSH
- proteolýza účinky léků účinky záření MeSH
- rekombinační oprava DNA účinky léků účinky záření MeSH
- rekombinasa Rad51 metabolismus MeSH
- sarkom metabolismus patologie terapie MeSH
- tetrahydroisochinoliny farmakologie MeSH
- trabektedin MeSH
- transport proteinů MeSH
- vazba proteinů MeSH
- viabilita buněk účinky léků účinky záření MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alkylační protinádorové látky MeSH
- dioxoly MeSH
- histony MeSH
- kaspasy MeSH
- protein BRCA2 MeSH
- rekombinasa Rad51 MeSH
- tetrahydroisochinoliny MeSH
- trabektedin MeSH
