Targeted Disruption of E6/p53 Binding Exerts Broad Activity and Synergism with Paclitaxel and Topotecan against HPV-Transformed Cancer Cells
High-risk human papillomaviruses (HR-HPV) are the etiological agents of almost all cervical cancer cases and a high percentage of head-and-neck malignancies. Although HPV vaccination can reduce cancer incidence, its coverage significantly differs among countries, and, therefore, in the next decades...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/1/193 |
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| author | Marta Celegato Lorenzo Messa Chiara Bertagnin Beatrice Mercorelli Arianna Loregian |
| author_facet | Marta Celegato Lorenzo Messa Chiara Bertagnin Beatrice Mercorelli Arianna Loregian |
| author_sort | Marta Celegato |
| collection | DOAJ |
| description | High-risk human papillomaviruses (HR-HPV) are the etiological agents of almost all cervical cancer cases and a high percentage of head-and-neck malignancies. Although HPV vaccination can reduce cancer incidence, its coverage significantly differs among countries, and, therefore, in the next decades HPV-related tumors will not likely be eradicated worldwide. Thus, the need of specific treatments persists, since no anti-HPV drug is yet available. We recently discovered a small molecule (Cpd12) able to inhibit the E6-mediated degradation of p53 through the disruption of E6/p53 binding in HPV16- and HPV18-positive cervical cancer cells. By employing several biochemical and cellular assays, here we show that Cpd12 is also active against cervical cancer cells transformed by other HR-HPV strains, such as HPV68 and HPV45, and against a HPV16-transformed head-and-neck cancer cell line, suggesting the possibility to employ Cpd12 as a targeted drug against a broad range of HPV-induced cancers. In these cancer cell lines, the antitumoral mechanism of action of Cpd12 involves p53-dependent cell cycle arrest, a senescent response, and inhibition of cancer cell migration. Finally, we show that Cpd12 can strongly synergize with taxanes and topoisomerase inhibitors, encouraging the evaluation of Cpd12 in preclinical studies for the targeted treatment of HPV-related carcinomas. |
| first_indexed | 2024-03-10T03:47:45Z |
| format | Article |
| id | doaj.art-df457d9de5694949a105410d5ba9181c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T03:47:45Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-df457d9de5694949a105410d5ba9181c2023-11-23T11:17:32ZengMDPI AGCancers2072-66942021-12-0114119310.3390/cancers14010193Targeted Disruption of E6/p53 Binding Exerts Broad Activity and Synergism with Paclitaxel and Topotecan against HPV-Transformed Cancer CellsMarta Celegato0Lorenzo Messa1Chiara Bertagnin2Beatrice Mercorelli3Arianna Loregian4Department of Molecular Medicine, University of Padua, 35121 Padua, ItalyDepartment of Molecular Medicine, University of Padua, 35121 Padua, ItalyDepartment of Molecular Medicine, University of Padua, 35121 Padua, ItalyDepartment of Molecular Medicine, University of Padua, 35121 Padua, ItalyDepartment of Molecular Medicine, University of Padua, 35121 Padua, ItalyHigh-risk human papillomaviruses (HR-HPV) are the etiological agents of almost all cervical cancer cases and a high percentage of head-and-neck malignancies. Although HPV vaccination can reduce cancer incidence, its coverage significantly differs among countries, and, therefore, in the next decades HPV-related tumors will not likely be eradicated worldwide. Thus, the need of specific treatments persists, since no anti-HPV drug is yet available. We recently discovered a small molecule (Cpd12) able to inhibit the E6-mediated degradation of p53 through the disruption of E6/p53 binding in HPV16- and HPV18-positive cervical cancer cells. By employing several biochemical and cellular assays, here we show that Cpd12 is also active against cervical cancer cells transformed by other HR-HPV strains, such as HPV68 and HPV45, and against a HPV16-transformed head-and-neck cancer cell line, suggesting the possibility to employ Cpd12 as a targeted drug against a broad range of HPV-induced cancers. In these cancer cell lines, the antitumoral mechanism of action of Cpd12 involves p53-dependent cell cycle arrest, a senescent response, and inhibition of cancer cell migration. Finally, we show that Cpd12 can strongly synergize with taxanes and topoisomerase inhibitors, encouraging the evaluation of Cpd12 in preclinical studies for the targeted treatment of HPV-related carcinomas.https://www.mdpi.com/2072-6694/14/1/193cervical cancerhead-and-neck cancerHPVtargeted therapysynergyPaclitaxel |
| spellingShingle | Marta Celegato Lorenzo Messa Chiara Bertagnin Beatrice Mercorelli Arianna Loregian Targeted Disruption of E6/p53 Binding Exerts Broad Activity and Synergism with Paclitaxel and Topotecan against HPV-Transformed Cancer Cells Cancers cervical cancer head-and-neck cancer HPV targeted therapy synergy Paclitaxel |
| title | Targeted Disruption of E6/p53 Binding Exerts Broad Activity and Synergism with Paclitaxel and Topotecan against HPV-Transformed Cancer Cells |
| title_full | Targeted Disruption of E6/p53 Binding Exerts Broad Activity and Synergism with Paclitaxel and Topotecan against HPV-Transformed Cancer Cells |
| title_fullStr | Targeted Disruption of E6/p53 Binding Exerts Broad Activity and Synergism with Paclitaxel and Topotecan against HPV-Transformed Cancer Cells |
| title_full_unstemmed | Targeted Disruption of E6/p53 Binding Exerts Broad Activity and Synergism with Paclitaxel and Topotecan against HPV-Transformed Cancer Cells |
| title_short | Targeted Disruption of E6/p53 Binding Exerts Broad Activity and Synergism with Paclitaxel and Topotecan against HPV-Transformed Cancer Cells |
| title_sort | targeted disruption of e6 p53 binding exerts broad activity and synergism with paclitaxel and topotecan against hpv transformed cancer cells |
| topic | cervical cancer head-and-neck cancer HPV targeted therapy synergy Paclitaxel |
| url | https://www.mdpi.com/2072-6694/14/1/193 |
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