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Hyperthermia adds to trabectedin effectiveness and thermal enhancement is associated with BRCA2 degradation and impairment of DNA homologous recombination repair
Author(s) -
Harnicek Dominique,
Kampmann Eric,
Lauber Kirsten,
Hennel Roman,
Cardoso Martins Ana Sofia,
Guo Yang,
Belka Claus,
Mörtl Simone,
Gallmeier Eike,
Kanaar Roland,
Mansmann Ulrich,
Hucl Tomas,
Lindner Lars H.,
Hiddemann Wolfgang,
Issels Rolf D.
Publication year - 2016
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30070
Subject(s) - trabectedin , cancer research , dna repair , soft tissue sarcoma , dna damage , hyperthermia , homologous recombination , medicine , sarcoma , biology , pathology , dna , genetics
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.