Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors
Type II testicular germ cell tumors (TGCT) are the most frequently diagnosed solid malignancy in young men. Up to 15% of patients with metastatic non-seminomas show cisplatin resistance and a very poor survival rate due to lacking treatment options. Transcriptional cyclin-dependent kinases (CDK) hav...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/7/1690 |
| _version_ | 1797440112802398208 |
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| author | Kai Funke Robert Düster Prince De-Graft Wilson Lena Arévalo Matthias Geyer Hubert Schorle |
| author_facet | Kai Funke Robert Düster Prince De-Graft Wilson Lena Arévalo Matthias Geyer Hubert Schorle |
| author_sort | Kai Funke |
| collection | DOAJ |
| description | Type II testicular germ cell tumors (TGCT) are the most frequently diagnosed solid malignancy in young men. Up to 15% of patients with metastatic non-seminomas show cisplatin resistance and a very poor survival rate due to lacking treatment options. Transcriptional cyclin-dependent kinases (CDK) have been shown to be effective targets in the treatment of different types of cancer. Here, we investigated the effects of the CDK inhibitors dinaciclib, flavopiridol, YKL-5-124, THZ1, NVP2, SY0351 and THZ531. An XTT viability assay revealed a strong cytotoxic impact of CDK7/12/13 inhibitor SY0351 and CDK9 inhibitor NVP2 on the TGCT wild-type cell lines (2102EP, NCCIT, TCam2) and the cisplatin-resistant cell lines (2102EP-R, NCCIT-R). The CDK7 inhibitor YKL-5-124 showed a strong impact on 2102EP, 2102EP-R, NCCIT and NCCIT-R cell lines, leaving the MPAF control cell line mostly unaffected. FACS-based analysis revealed mild effects on the cell cycle of 2102EP and TCam2 cells after SY0351, YKL-5-124 or NVP2 treatment. Molecular analysis showed a cell-line-specific response for SY0351 and NVP2 inhibition while YKL-5-124 induced similar molecular changes in 2102EP, TCam2 and MPAF cells. Thus, after TGCT subtype determination, CDK inhibitors might be a potential alternative for optimized and individualized therapy independent of chemotherapy sensitivity. |
| first_indexed | 2024-03-09T12:03:26Z |
| format | Article |
| id | doaj.art-2585edb0bf5445399c683f95cf4a7924 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T12:03:26Z |
| publishDate | 2022-03-01 |
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| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2585edb0bf5445399c683f95cf4a79242023-11-30T23:00:39ZengMDPI AGCancers2072-66942022-03-01147169010.3390/cancers14071690Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell TumorsKai Funke0Robert Düster1Prince De-Graft Wilson2Lena Arévalo3Matthias Geyer4Hubert Schorle5Department of Developmental Pathology, Institute of Pathology, University Hospital Bonn, 53127 Bonn, GermanyThe Institute of Structural Biology, University of Bonn, 53127 Bonn, GermanyDepartment of Developmental Pathology, Institute of Pathology, University Hospital Bonn, 53127 Bonn, GermanyDepartment of Developmental Pathology, Institute of Pathology, University Hospital Bonn, 53127 Bonn, GermanyThe Institute of Structural Biology, University of Bonn, 53127 Bonn, GermanyDepartment of Developmental Pathology, Institute of Pathology, University Hospital Bonn, 53127 Bonn, GermanyType II testicular germ cell tumors (TGCT) are the most frequently diagnosed solid malignancy in young men. Up to 15% of patients with metastatic non-seminomas show cisplatin resistance and a very poor survival rate due to lacking treatment options. Transcriptional cyclin-dependent kinases (CDK) have been shown to be effective targets in the treatment of different types of cancer. Here, we investigated the effects of the CDK inhibitors dinaciclib, flavopiridol, YKL-5-124, THZ1, NVP2, SY0351 and THZ531. An XTT viability assay revealed a strong cytotoxic impact of CDK7/12/13 inhibitor SY0351 and CDK9 inhibitor NVP2 on the TGCT wild-type cell lines (2102EP, NCCIT, TCam2) and the cisplatin-resistant cell lines (2102EP-R, NCCIT-R). The CDK7 inhibitor YKL-5-124 showed a strong impact on 2102EP, 2102EP-R, NCCIT and NCCIT-R cell lines, leaving the MPAF control cell line mostly unaffected. FACS-based analysis revealed mild effects on the cell cycle of 2102EP and TCam2 cells after SY0351, YKL-5-124 or NVP2 treatment. Molecular analysis showed a cell-line-specific response for SY0351 and NVP2 inhibition while YKL-5-124 induced similar molecular changes in 2102EP, TCam2 and MPAF cells. Thus, after TGCT subtype determination, CDK inhibitors might be a potential alternative for optimized and individualized therapy independent of chemotherapy sensitivity.https://www.mdpi.com/2072-6694/14/7/1690testicular germ cell tumorstranscriptional cyclin-dependent kinase inhibitorsCDK inhibitorsNVP2SY0351YKL-5-124 |
| spellingShingle | Kai Funke Robert Düster Prince De-Graft Wilson Lena Arévalo Matthias Geyer Hubert Schorle Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors Cancers testicular germ cell tumors transcriptional cyclin-dependent kinase inhibitors CDK inhibitors NVP2 SY0351 YKL-5-124 |
| title | Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors |
| title_full | Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors |
| title_fullStr | Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors |
| title_full_unstemmed | Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors |
| title_short | Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors |
| title_sort | transcriptional cdk inhibitors as potential treatment option for testicular germ cell tumors |
| topic | testicular germ cell tumors transcriptional cyclin-dependent kinase inhibitors CDK inhibitors NVP2 SY0351 YKL-5-124 |
| url | https://www.mdpi.com/2072-6694/14/7/1690 |
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