Cisplatin Protein Binding Partners and Their Relevance for Platinum Drug Sensitivity
Cisplatin is a widely used drug in the treatment of various solid tumors, such as ovarian cancer. However, while the acquired resistance significantly limits the success of therapy, some tumors, such as colorectal cancer, are intrinsically insensitive to cisplatin. Only a small amount of intracellul...
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MDPI AG
2020-05-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/6/1322 |
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| author | Sophie Möltgen Eleonora Piumatti Giuseppe M. Massafra Sabine Metzger Ulrich Jaehde Ganna V. Kalayda |
| author_facet | Sophie Möltgen Eleonora Piumatti Giuseppe M. Massafra Sabine Metzger Ulrich Jaehde Ganna V. Kalayda |
| author_sort | Sophie Möltgen |
| collection | DOAJ |
| description | Cisplatin is a widely used drug in the treatment of various solid tumors, such as ovarian cancer. However, while the acquired resistance significantly limits the success of therapy, some tumors, such as colorectal cancer, are intrinsically insensitive to cisplatin. Only a small amount of intracellular platinum binds to the target—genomic DNA. The fate of the remaining drug is largely obscure. This work aimed to identify the cytosolic protein binding partners of cisplatin in ovarian and colorectal cancer cells and to evaluate their relevance for cell sensitivity to cisplatin and oxaliplatin. Using the fluorescent cisplatin analog BODIPY-cisplatin, two-dimensional gel electrophoresis, and mass spectrometry, we identified the protein binding partners in A2780 and cisplatin-resistant A2780cis ovarian carcinoma, as well as in HCT-8 and oxaliplatin-resistant HCT-8ox colorectal cell lines. Vimentin, only identified in ovarian cancer cells; growth factor receptor-bound protein 2, only identified in colorectal cancer cells; and glutathione-S-transferase π, identified in all four cell lines, were further investigated. The effect of pharmacological inhibition and siRNA-mediated knockdown on cytotoxicity was studied to assess the relevance of these binding partners. The silencing of glutathione-S-transferase π significantly sensitized intrinsically resistant HCT-8 and HCT-8ox cells to cisplatin, suggesting a possible involvement of the protein in the resistance of colorectal cancer cells to the drug. The inhibition of vimentin with FiVe1 resulted in a significant sensitization of A2780 and A2780cis cells to cisplatin, revealing new possibilities for improving the chemosensitivity of ovarian cancer cells. |
| first_indexed | 2024-03-10T19:35:54Z |
| format | Article |
| id | doaj.art-ab749920f29540d0badb67fccf0e84e7 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T19:35:54Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-ab749920f29540d0badb67fccf0e84e72023-11-20T01:44:41ZengMDPI AGCells2073-44092020-05-0196132210.3390/cells9061322Cisplatin Protein Binding Partners and Their Relevance for Platinum Drug SensitivitySophie Möltgen0Eleonora Piumatti1Giuseppe M. Massafra2Sabine Metzger3Ulrich Jaehde4Ganna V. Kalayda5Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, 53113 Bonn, GermanyDepartment of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, 53113 Bonn, GermanyDepartment of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, 53113 Bonn, GermanyCologne Biocenter, MS Facility, University of Cologne, 50923 Cologne, GermanyDepartment of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, 53113 Bonn, GermanyDepartment of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, 53113 Bonn, GermanyCisplatin is a widely used drug in the treatment of various solid tumors, such as ovarian cancer. However, while the acquired resistance significantly limits the success of therapy, some tumors, such as colorectal cancer, are intrinsically insensitive to cisplatin. Only a small amount of intracellular platinum binds to the target—genomic DNA. The fate of the remaining drug is largely obscure. This work aimed to identify the cytosolic protein binding partners of cisplatin in ovarian and colorectal cancer cells and to evaluate their relevance for cell sensitivity to cisplatin and oxaliplatin. Using the fluorescent cisplatin analog BODIPY-cisplatin, two-dimensional gel electrophoresis, and mass spectrometry, we identified the protein binding partners in A2780 and cisplatin-resistant A2780cis ovarian carcinoma, as well as in HCT-8 and oxaliplatin-resistant HCT-8ox colorectal cell lines. Vimentin, only identified in ovarian cancer cells; growth factor receptor-bound protein 2, only identified in colorectal cancer cells; and glutathione-S-transferase π, identified in all four cell lines, were further investigated. The effect of pharmacological inhibition and siRNA-mediated knockdown on cytotoxicity was studied to assess the relevance of these binding partners. The silencing of glutathione-S-transferase π significantly sensitized intrinsically resistant HCT-8 and HCT-8ox cells to cisplatin, suggesting a possible involvement of the protein in the resistance of colorectal cancer cells to the drug. The inhibition of vimentin with FiVe1 resulted in a significant sensitization of A2780 and A2780cis cells to cisplatin, revealing new possibilities for improving the chemosensitivity of ovarian cancer cells.https://www.mdpi.com/2073-4409/9/6/1322cisplatin resistanceBODIPY-cisplatinoxaliplatinvimentinglutathione-S-transferase πgrowth factor receptor-bound protein 2 |
| spellingShingle | Sophie Möltgen Eleonora Piumatti Giuseppe M. Massafra Sabine Metzger Ulrich Jaehde Ganna V. Kalayda Cisplatin Protein Binding Partners and Their Relevance for Platinum Drug Sensitivity Cells cisplatin resistance BODIPY-cisplatin oxaliplatin vimentin glutathione-S-transferase π growth factor receptor-bound protein 2 |
| title | Cisplatin Protein Binding Partners and Their Relevance for Platinum Drug Sensitivity |
| title_full | Cisplatin Protein Binding Partners and Their Relevance for Platinum Drug Sensitivity |
| title_fullStr | Cisplatin Protein Binding Partners and Their Relevance for Platinum Drug Sensitivity |
| title_full_unstemmed | Cisplatin Protein Binding Partners and Their Relevance for Platinum Drug Sensitivity |
| title_short | Cisplatin Protein Binding Partners and Their Relevance for Platinum Drug Sensitivity |
| title_sort | cisplatin protein binding partners and their relevance for platinum drug sensitivity |
| topic | cisplatin resistance BODIPY-cisplatin oxaliplatin vimentin glutathione-S-transferase π growth factor receptor-bound protein 2 |
| url | https://www.mdpi.com/2073-4409/9/6/1322 |
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