Clickable Cisplatin Derivatives as Versatile Tools to Probe the DNA Damage Response to Chemotherapy
Cisplatin induces DNA crosslinks that are highly cytotoxic. Hence, platinum complexes are frequently used in the treatment of a broad range of cancers. Efficiency of cisplatin treatment is limited by the tumor-specific DNA damage response to the generated lesions. We reasoned that better tools to in...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.874201/full |
| _version_ | 1811245439974899712 |
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| author | Amandine Moretton Amandine Moretton Jana Slyskova Jana Slyskova Marwan E. Simaan Marwan E. Simaan Marwan E. Simaan Emili A. Arasa-Verge Mathilde Meyenberg Mathilde Meyenberg D. Alonso Cerrón-Infantes D. Alonso Cerrón-Infantes D. Alonso Cerrón-Infantes D. Alonso Cerrón-Infantes Miriam M. Unterlass Miriam M. Unterlass Miriam M. Unterlass Miriam M. Unterlass Joanna I. Loizou Joanna I. Loizou |
| author_facet | Amandine Moretton Amandine Moretton Jana Slyskova Jana Slyskova Marwan E. Simaan Marwan E. Simaan Marwan E. Simaan Emili A. Arasa-Verge Mathilde Meyenberg Mathilde Meyenberg D. Alonso Cerrón-Infantes D. Alonso Cerrón-Infantes D. Alonso Cerrón-Infantes D. Alonso Cerrón-Infantes Miriam M. Unterlass Miriam M. Unterlass Miriam M. Unterlass Miriam M. Unterlass Joanna I. Loizou Joanna I. Loizou |
| author_sort | Amandine Moretton |
| collection | DOAJ |
| description | Cisplatin induces DNA crosslinks that are highly cytotoxic. Hence, platinum complexes are frequently used in the treatment of a broad range of cancers. Efficiency of cisplatin treatment is limited by the tumor-specific DNA damage response to the generated lesions. We reasoned that better tools to investigate the repair of DNA crosslinks induced by cisplatin would therefore be highly useful in addressing drug limitations. Here, we synthesized a series of cisplatin derivatives that are compatible with click chemistry, thus allowing visualization and isolation of DNA-platinum crosslinks from cells to study cellular responses. We prioritized one alkyne and one azide Pt(II) derivative, Pt-alkyne-53 and Pt-azide-64, for further biological characterization. We demonstrate that both compounds bind DNA and generate DNA lesions and that the viability of treated cells depends on the active DNA repair machinery. We also show that the compounds are clickable with both a fluorescent probe as well as biotin, thus they can be visualized in cells, and their ability to induce crosslinks in genomic DNA can be quantified. Finally, we show that Pt-alkyne-53 can be used to identify DNA repair proteins that bind within its proximity to facilitate its removal from DNA. The compounds we report here can be used as valuable experimental tools to investigate the DNA damage response to platinum complexes and hence might shed light on mechanisms of chemoresistance. |
| first_indexed | 2024-04-12T14:39:06Z |
| format | Article |
| id | doaj.art-a272064995c74462a8275450613f4f13 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T14:39:06Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-a272064995c74462a8275450613f4f132022-12-22T03:28:55ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-06-011210.3389/fonc.2022.874201874201Clickable Cisplatin Derivatives as Versatile Tools to Probe the DNA Damage Response to ChemotherapyAmandine Moretton0Amandine Moretton1Jana Slyskova2Jana Slyskova3Marwan E. Simaan4Marwan E. Simaan5Marwan E. Simaan6Emili A. Arasa-Verge7Mathilde Meyenberg8Mathilde Meyenberg9D. Alonso Cerrón-Infantes10D. Alonso Cerrón-Infantes11D. Alonso Cerrón-Infantes12D. Alonso Cerrón-Infantes13Miriam M. Unterlass14Miriam M. Unterlass15Miriam M. Unterlass16Miriam M. Unterlass17Joanna I. Loizou18Joanna I. Loizou19Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, AustriaCenter for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, AustriaInstitute of Materials Chemistry, Technische Universität Wien, Vienna, AustriaInstitute of Applied Synthetic Chemistry, Technische Universität Wien, Vienna, AustriaCenter for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, AustriaCenter for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, AustriaInstitute of Materials Chemistry, Technische Universität Wien, Vienna, AustriaInstitute of Applied Synthetic Chemistry, Technische Universität Wien, Vienna, AustriaDepartment of Chemistry, Solid State Chemistry, Universität Konstanz, Konstanz, GermanyCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, AustriaInstitute of Materials Chemistry, Technische Universität Wien, Vienna, AustriaInstitute of Applied Synthetic Chemistry, Technische Universität Wien, Vienna, AustriaDepartment of Chemistry, Solid State Chemistry, Universität Konstanz, Konstanz, GermanyCenter for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, AustriaCisplatin induces DNA crosslinks that are highly cytotoxic. Hence, platinum complexes are frequently used in the treatment of a broad range of cancers. Efficiency of cisplatin treatment is limited by the tumor-specific DNA damage response to the generated lesions. We reasoned that better tools to investigate the repair of DNA crosslinks induced by cisplatin would therefore be highly useful in addressing drug limitations. Here, we synthesized a series of cisplatin derivatives that are compatible with click chemistry, thus allowing visualization and isolation of DNA-platinum crosslinks from cells to study cellular responses. We prioritized one alkyne and one azide Pt(II) derivative, Pt-alkyne-53 and Pt-azide-64, for further biological characterization. We demonstrate that both compounds bind DNA and generate DNA lesions and that the viability of treated cells depends on the active DNA repair machinery. We also show that the compounds are clickable with both a fluorescent probe as well as biotin, thus they can be visualized in cells, and their ability to induce crosslinks in genomic DNA can be quantified. Finally, we show that Pt-alkyne-53 can be used to identify DNA repair proteins that bind within its proximity to facilitate its removal from DNA. The compounds we report here can be used as valuable experimental tools to investigate the DNA damage response to platinum complexes and hence might shed light on mechanisms of chemoresistance.https://www.frontiersin.org/articles/10.3389/fonc.2022.874201/fullcisplatinchemotherapychemoresistanceDNA DamageDNA crosslinksDNA repair |
| spellingShingle | Amandine Moretton Amandine Moretton Jana Slyskova Jana Slyskova Marwan E. Simaan Marwan E. Simaan Marwan E. Simaan Emili A. Arasa-Verge Mathilde Meyenberg Mathilde Meyenberg D. Alonso Cerrón-Infantes D. Alonso Cerrón-Infantes D. Alonso Cerrón-Infantes D. Alonso Cerrón-Infantes Miriam M. Unterlass Miriam M. Unterlass Miriam M. Unterlass Miriam M. Unterlass Joanna I. Loizou Joanna I. Loizou Clickable Cisplatin Derivatives as Versatile Tools to Probe the DNA Damage Response to Chemotherapy Frontiers in Oncology cisplatin chemotherapy chemoresistance DNA Damage DNA crosslinks DNA repair |
| title | Clickable Cisplatin Derivatives as Versatile Tools to Probe the DNA Damage Response to Chemotherapy |
| title_full | Clickable Cisplatin Derivatives as Versatile Tools to Probe the DNA Damage Response to Chemotherapy |
| title_fullStr | Clickable Cisplatin Derivatives as Versatile Tools to Probe the DNA Damage Response to Chemotherapy |
| title_full_unstemmed | Clickable Cisplatin Derivatives as Versatile Tools to Probe the DNA Damage Response to Chemotherapy |
| title_short | Clickable Cisplatin Derivatives as Versatile Tools to Probe the DNA Damage Response to Chemotherapy |
| title_sort | clickable cisplatin derivatives as versatile tools to probe the dna damage response to chemotherapy |
| topic | cisplatin chemotherapy chemoresistance DNA Damage DNA crosslinks DNA repair |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.874201/full |
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