Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance
Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. The combination of cisplatin (CDDP) plus cetuximab (CX) is one of the standard first-line treatments in this disease. However, this therapeutic regimen is often associated with h...
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| Format: | Article |
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Frontiers Media S.A.
2020-08-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fcell.2020.00732/full |
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| author | Federica Iannelli Andrea Ilaria Zotti Maria Serena Roca Laura Grumetti Rita Lombardi Tania Moccia Carlo Vitagliano Maria Rita Milone Chiara Ciardiello Francesca Bruzzese Alessandra Leone Ernesta Cavalcanti Rossella De Cecio Giuseppina Iachetta Salvatore Valiante Franco Ionna Francesco Caponigro Elena Di Gennaro Alfredo Budillon |
| author_facet | Federica Iannelli Andrea Ilaria Zotti Maria Serena Roca Laura Grumetti Rita Lombardi Tania Moccia Carlo Vitagliano Maria Rita Milone Chiara Ciardiello Francesca Bruzzese Alessandra Leone Ernesta Cavalcanti Rossella De Cecio Giuseppina Iachetta Salvatore Valiante Franco Ionna Francesco Caponigro Elena Di Gennaro Alfredo Budillon |
| author_sort | Federica Iannelli |
| collection | DOAJ |
| description | Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. The combination of cisplatin (CDDP) plus cetuximab (CX) is one of the standard first-line treatments in this disease. However, this therapeutic regimen is often associated with high toxicity and resistance, suggesting that new combinatorial strategies are needed to improve its therapeutic index. In our study, we evaluated the antitumor effects of valproic acid (VPA), a well-known antiepileptic agent with histone deacetylase inhibitory activity, in combination with CDDP/CX doublet in head and neck squamous cell carcinoma (HNSCC) models. We demonstrated, in HNSCC cell lines, but not in normal human fibroblasts, that simultaneous exposure to equitoxic doses of VPA plus CDDP/CX resulted in a clear synergistic antiproliferative and pro-apoptotic effects. The synergistic antitumor effect was confirmed in four different 3D-self-assembled spheroid models, suggesting the ability of the combined approach to affect also the cancer stem cells compartment. Mechanistically, VPA enhanced DNA damage in combination treatment by reducing the mRNA expression of ERCC Excision Repair 1, a critical player in DNA repair, and by increasing CDDP intracellular concentration via upregulation at transcriptional level of CDDP influx channel copper transporter 1 and downregulation of the ATPAse ATP7B involved in CDDP-export. Valproic acid also induced a dose-dependent downregulation of epidermal growth factor receptor (EGFR) expression and of MAPK and AKT downstream signaling pathways and prevent CDDP- and/or CX-induced EGFR nuclear translocation, a well-known mechanism of resistance to chemotherapy. Indeed, VPA impaired the transcription of genes induced by non-canonical activity of nuclear EGFR, such as cyclin D1 and thymidylate synthase. Finally, we confirmed the synergistic antitumor effect also in vivo in both heterotopic and orthotopic models, demonstrating that the combined treatment completely blocked HNSCC xenograft tumors growth in nude mice. Overall, the introduction of a safe and generic drug such as VPA into the conventional treatment for R/M HNSCC represents an innovative and feasible antitumor strategy that warrants further clinical evaluation. A phase II clinical trial exploring the combination of VPA and CDDP/CX in R/M HNSCC patients is currently ongoing in our institute. |
| first_indexed | 2024-12-10T23:26:51Z |
| format | Article |
| id | doaj.art-322d6309ee924382b66d5dcdaf5dbda5 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-10T23:26:51Z |
| publishDate | 2020-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-322d6309ee924382b66d5dcdaf5dbda52022-12-22T01:29:33ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2020-08-01810.3389/fcell.2020.00732548161Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of ResistanceFederica Iannelli0Andrea Ilaria Zotti1Maria Serena Roca2Laura Grumetti3Rita Lombardi4Tania Moccia5Carlo Vitagliano6Maria Rita Milone7Chiara Ciardiello8Francesca Bruzzese9Alessandra Leone10Ernesta Cavalcanti11Rossella De Cecio12Giuseppina Iachetta13Salvatore Valiante14Franco Ionna15Francesco Caponigro16Elena Di Gennaro17Alfredo Budillon18Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyExperimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyExperimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyExperimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyExperimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyExperimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyExperimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyExperimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyExperimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyExperimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyExperimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyLaboratory Medicine Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyPathology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyDepartment of Biology, University of Naples Federico II, Naples, ItalyDepartment of Biology, University of Naples Federico II, Naples, ItalyMaxillo-facial & ENT Surgery Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyHead and Neck Medical Oncology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyExperimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyExperimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, ItalyRecurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. The combination of cisplatin (CDDP) plus cetuximab (CX) is one of the standard first-line treatments in this disease. However, this therapeutic regimen is often associated with high toxicity and resistance, suggesting that new combinatorial strategies are needed to improve its therapeutic index. In our study, we evaluated the antitumor effects of valproic acid (VPA), a well-known antiepileptic agent with histone deacetylase inhibitory activity, in combination with CDDP/CX doublet in head and neck squamous cell carcinoma (HNSCC) models. We demonstrated, in HNSCC cell lines, but not in normal human fibroblasts, that simultaneous exposure to equitoxic doses of VPA plus CDDP/CX resulted in a clear synergistic antiproliferative and pro-apoptotic effects. The synergistic antitumor effect was confirmed in four different 3D-self-assembled spheroid models, suggesting the ability of the combined approach to affect also the cancer stem cells compartment. Mechanistically, VPA enhanced DNA damage in combination treatment by reducing the mRNA expression of ERCC Excision Repair 1, a critical player in DNA repair, and by increasing CDDP intracellular concentration via upregulation at transcriptional level of CDDP influx channel copper transporter 1 and downregulation of the ATPAse ATP7B involved in CDDP-export. Valproic acid also induced a dose-dependent downregulation of epidermal growth factor receptor (EGFR) expression and of MAPK and AKT downstream signaling pathways and prevent CDDP- and/or CX-induced EGFR nuclear translocation, a well-known mechanism of resistance to chemotherapy. Indeed, VPA impaired the transcription of genes induced by non-canonical activity of nuclear EGFR, such as cyclin D1 and thymidylate synthase. Finally, we confirmed the synergistic antitumor effect also in vivo in both heterotopic and orthotopic models, demonstrating that the combined treatment completely blocked HNSCC xenograft tumors growth in nude mice. Overall, the introduction of a safe and generic drug such as VPA into the conventional treatment for R/M HNSCC represents an innovative and feasible antitumor strategy that warrants further clinical evaluation. A phase II clinical trial exploring the combination of VPA and CDDP/CX in R/M HNSCC patients is currently ongoing in our institute.https://www.frontiersin.org/article/10.3389/fcell.2020.00732/fullHDAC inhibitorvalproic acidcisplatincetuximabepidermal growth factor receptorhead and neck squamous cell carcinoma |
| spellingShingle | Federica Iannelli Andrea Ilaria Zotti Maria Serena Roca Laura Grumetti Rita Lombardi Tania Moccia Carlo Vitagliano Maria Rita Milone Chiara Ciardiello Francesca Bruzzese Alessandra Leone Ernesta Cavalcanti Rossella De Cecio Giuseppina Iachetta Salvatore Valiante Franco Ionna Francesco Caponigro Elena Di Gennaro Alfredo Budillon Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance Frontiers in Cell and Developmental Biology HDAC inhibitor valproic acid cisplatin cetuximab epidermal growth factor receptor head and neck squamous cell carcinoma |
| title | Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance |
| title_full | Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance |
| title_fullStr | Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance |
| title_full_unstemmed | Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance |
| title_short | Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance |
| title_sort | valproic acid synergizes with cisplatin and cetuximab in vitro and in vivo in head and neck cancer by targeting the mechanisms of resistance |
| topic | HDAC inhibitor valproic acid cisplatin cetuximab epidermal growth factor receptor head and neck squamous cell carcinoma |
| url | https://www.frontiersin.org/article/10.3389/fcell.2020.00732/full |
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