Hyperthermia adds to trabectedin effectiveness and thermal enhancement is associated with BRCA2 degradation and impairment of DNA homologous recombination repair

Autor: Harnicek, D, Kampmann, E, Lauber, K, Hennel, R, Martins, ASC, Guo, Y, Belka, C, Mortl, S, Gallmeier, E, Kanaar, Roland, Mansmann, U, Hucl, T, Lindner, LH, Hiddemann, W, Issels, RD
Přispěvatelé: Molecular Genetics, Radiotherapy
Rok vydání: 2015
Předmět:
Zdroj: Int. J. Cancer 139, 467-479 (2016)
International Journal of Cancer, 139(2), 467-479. Wiley-Liss Inc.
ISSN: 1097-0215
0020-7136
Popis: The tetrahydroisoquinoline trabectedin is a marine compound with approved activity against human soft-tissue sarcoma. It exerts anti-proliferative activity mainly by specific binding to the DNA and inducing DNA double-strand breaks (DSB). Since 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°C 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.
Databáze: OpenAIRE
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