PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models
| Autor: | Lucia Napione, Maria Serena Benassi, Giovanna Chiorino, Ymera Pignochino, Loretta Gammaitoni, Giovanni Grignani, Danilo Galizia, Erica Palesandro, Lorenzo D'Ambrosio, Marta Canta, Sandra Aliberti, Carmine Dell'Aglio, Barbara Pasini, Giulia Chiabotto, Francesca Vignolo Lutati, Annalisa Lorenzato, Marco Basiricò, Dario Sangiolo, Massimo Aglietta, Paola Boccone, Federica Capozzi, Sara Miano |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Cell cycle checkpoint Poly (ADP-Ribose) Polymerase-1 Apoptosis Pharmacology Piperazines Mice chemistry.chemical_compound 0302 clinical medicine PARP1 Olaparib Predictive biomarkers Tetrahydroisoquinolines Trabectedin Comparative Genomic Hybridization Sarcoma lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Gene Expression Regulation Neoplastic Oncology 030220 oncology & carcinogenesis Molecular Medicine medicine.symptom medicine.drug DNA damage Dioxoles Biology lcsh:RC254-282 03 medical and health sciences Cell Line Tumor Biomarkers Tumor medicine Animals Humans Gene silencing Bone and soft tissue sarcomas DNA-damaging agents Drug synergism PARP1 inhibitors Research Xenograft Model Antitumor Assays Molecular medicine 030104 developmental biology chemistry Mechanism of action Cancer research Phthalazines DNA Damage |
| Zdroj: | Molecular Cancer Molecular Cancer, Vol 16, Iss 1, Pp 1-15 (2017) |
| Popis: | Background Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death. Methods We investigated trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role. Results Trabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with trabectedin and we confirmed the antitumor and antimetastatic activity of trabectedin/olaparib combination in mice models. However, we observed different degree of trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing. Conclusions PARP1 inhibition potentiated trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves clinical evaluation. Electronic supplementary material The online version of this article (doi:10.1186/s12943-017-0652-5) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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