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PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models

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...

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Autores principales: Pignochino, Ymera, Capozzi, Federica, D’Ambrosio, Lorenzo, Dell’Aglio, Carmine, Basiricò, Marco, Canta, Marta, Lorenzato, Annalisa, Vignolo Lutati, Francesca, Aliberti, Sandra, Palesandro, Erica, Boccone, Paola, Galizia, Danilo, Miano, Sara, Chiabotto, Giulia, Napione, Lucia, Gammaitoni, Loretta, Sangiolo, Dario, Benassi, Maria Serena, Pasini, Barbara, Chiorino, Giovanna, Aglietta, Massimo, Grignani, Giovanni
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410089/
https://www.ncbi.nlm.nih.gov/pubmed/28454547
http://dx.doi.org/10.1186/s12943-017-0652-5
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author Pignochino, Ymera
Capozzi, Federica
D’Ambrosio, Lorenzo
Dell’Aglio, Carmine
Basiricò, Marco
Canta, Marta
Lorenzato, Annalisa
Vignolo Lutati, Francesca
Aliberti, Sandra
Palesandro, Erica
Boccone, Paola
Galizia, Danilo
Miano, Sara
Chiabotto, Giulia
Napione, Lucia
Gammaitoni, Loretta
Sangiolo, Dario
Benassi, Maria Serena
Pasini, Barbara
Chiorino, Giovanna
Aglietta, Massimo
Grignani, Giovanni
author_facet Pignochino, Ymera
Capozzi, Federica
D’Ambrosio, Lorenzo
Dell’Aglio, Carmine
Basiricò, Marco
Canta, Marta
Lorenzato, Annalisa
Vignolo Lutati, Francesca
Aliberti, Sandra
Palesandro, Erica
Boccone, Paola
Galizia, Danilo
Miano, Sara
Chiabotto, Giulia
Napione, Lucia
Gammaitoni, Loretta
Sangiolo, Dario
Benassi, Maria Serena
Pasini, Barbara
Chiorino, Giovanna
Aglietta, Massimo
Grignani, Giovanni
author_sort Pignochino, Ymera
collection PubMed
description 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.
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spelling pubmed-54100892017-05-02 PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models Pignochino, Ymera Capozzi, Federica D’Ambrosio, Lorenzo Dell’Aglio, Carmine Basiricò, Marco Canta, Marta Lorenzato, Annalisa Vignolo Lutati, Francesca Aliberti, Sandra Palesandro, Erica Boccone, Paola Galizia, Danilo Miano, Sara Chiabotto, Giulia Napione, Lucia Gammaitoni, Loretta Sangiolo, Dario Benassi, Maria Serena Pasini, Barbara Chiorino, Giovanna Aglietta, Massimo Grignani, Giovanni Mol Cancer Research 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. BioMed Central 2017-04-28 /pmc/articles/PMC5410089/ /pubmed/28454547 http://dx.doi.org/10.1186/s12943-017-0652-5 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Pignochino, Ymera
Capozzi, Federica
D’Ambrosio, Lorenzo
Dell’Aglio, Carmine
Basiricò, Marco
Canta, Marta
Lorenzato, Annalisa
Vignolo Lutati, Francesca
Aliberti, Sandra
Palesandro, Erica
Boccone, Paola
Galizia, Danilo
Miano, Sara
Chiabotto, Giulia
Napione, Lucia
Gammaitoni, Loretta
Sangiolo, Dario
Benassi, Maria Serena
Pasini, Barbara
Chiorino, Giovanna
Aglietta, Massimo
Grignani, Giovanni
PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models
title PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models
title_full PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models
title_fullStr PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models
title_full_unstemmed PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models
title_short PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models
title_sort parp1 expression drives the synergistic antitumor activity of trabectedin and parp1 inhibitors in sarcoma preclinical models
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410089/
https://www.ncbi.nlm.nih.gov/pubmed/28454547
http://dx.doi.org/10.1186/s12943-017-0652-5
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