PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models
Abstract 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-break...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-04-01
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| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12943-017-0652-5 |
| _version_ | 1818031227417919488 |
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| author | Ymera Pignochino Federica Capozzi Lorenzo D’Ambrosio Carmine Dell’Aglio Marco Basiricò Marta Canta Annalisa Lorenzato Francesca Vignolo Lutati Sandra Aliberti Erica Palesandro Paola Boccone Danilo Galizia Sara Miano Giulia Chiabotto Lucia Napione Loretta Gammaitoni Dario Sangiolo Maria Serena Benassi Barbara Pasini Giovanna Chiorino Massimo Aglietta Giovanni Grignani |
| author_facet | Ymera Pignochino Federica Capozzi Lorenzo D’Ambrosio Carmine Dell’Aglio Marco Basiricò Marta Canta Annalisa Lorenzato Francesca Vignolo Lutati Sandra Aliberti Erica Palesandro Paola Boccone Danilo Galizia Sara Miano Giulia Chiabotto Lucia Napione Loretta Gammaitoni Dario Sangiolo Maria Serena Benassi Barbara Pasini Giovanna Chiorino Massimo Aglietta Giovanni Grignani |
| author_sort | Ymera Pignochino |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-10T05:48:07Z |
| format | Article |
| id | doaj.art-e058c6685da841f684afb510424d766a |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-10T05:48:07Z |
| publishDate | 2017-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-e058c6685da841f684afb510424d766a2022-12-22T02:00:06ZengBMCMolecular Cancer1476-45982017-04-0116111510.1186/s12943-017-0652-5PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical modelsYmera Pignochino0Federica Capozzi1Lorenzo D’Ambrosio2Carmine Dell’Aglio3Marco Basiricò4Marta Canta5Annalisa Lorenzato6Francesca Vignolo Lutati7Sandra Aliberti8Erica Palesandro9Paola Boccone10Danilo Galizia11Sara Miano12Giulia Chiabotto13Lucia Napione14Loretta Gammaitoni15Dario Sangiolo16Maria Serena Benassi17Barbara Pasini18Giovanna Chiorino19Massimo Aglietta20Giovanni Grignani21Sarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCSSarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCSSarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCSPathology Unit, Candiolo Cancer Institute - FPO, IRCCSMedical Oncology, Candiolo Cancer Institute – FPO, IRCCSSarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCSDepartment of Oncology, University of Torino Medical SchoolDepartment of Genetics, Biology and Biochemistry, University of TorinoSarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCSSarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCSSarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCSSarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCSSarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCSSarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCSDepartment of Oncology, University of Torino Medical SchoolLaboratory of Vascular Oncology, Candiolo Cancer Institute - FPO, IRCCSDepartment of Oncology, University of Torino Medical SchoolExperimental Oncology Laboratory, IRCCS Istituto Ortopedico RizzoliDepartment of Genetics, Biology and Biochemistry, University of TorinoCancer Genomics Lab, Fondazione Edo ed Elvo TempiaDepartment of Oncology, University of Torino Medical SchoolSarcoma Unit, Medical Oncology, Candiolo Cancer Institute - FPO, IRCCSAbstract 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.http://link.springer.com/article/10.1186/s12943-017-0652-5Predictive biomarkersPARP1 inhibitorsDNA-damaging agentsTrabectedinOlaparibBone and soft tissue sarcomas |
| spellingShingle | Ymera Pignochino Federica Capozzi Lorenzo D’Ambrosio Carmine Dell’Aglio Marco Basiricò Marta Canta Annalisa Lorenzato Francesca Vignolo Lutati Sandra Aliberti Erica Palesandro Paola Boccone Danilo Galizia Sara Miano Giulia Chiabotto Lucia Napione Loretta Gammaitoni Dario Sangiolo Maria Serena Benassi Barbara Pasini Giovanna Chiorino Massimo Aglietta Giovanni Grignani PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models Molecular Cancer Predictive biomarkers PARP1 inhibitors DNA-damaging agents Trabectedin Olaparib Bone and soft tissue sarcomas |
| 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 | Predictive biomarkers PARP1 inhibitors DNA-damaging agents Trabectedin Olaparib Bone and soft tissue sarcomas |
| url | http://link.springer.com/article/10.1186/s12943-017-0652-5 |
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