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Decitabine Rescues Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma

Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) reduces survival. In this study we hypothesized that methylation of key genes mediates cisplatin resistance. We determined whether a demethylating drug, decitabine, could augment the anti-proliferative and apoptotic effects of cis...

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Autores principales: Viet, Chi T., Dang, Dongmin, Achdjian, Stacy, Ye, Yi, Katz, Samuel G., Schmidt, Brian L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229295/
https://www.ncbi.nlm.nih.gov/pubmed/25391133
http://dx.doi.org/10.1371/journal.pone.0112880
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author Viet, Chi T.
Dang, Dongmin
Achdjian, Stacy
Ye, Yi
Katz, Samuel G.
Schmidt, Brian L.
author_facet Viet, Chi T.
Dang, Dongmin
Achdjian, Stacy
Ye, Yi
Katz, Samuel G.
Schmidt, Brian L.
author_sort Viet, Chi T.
collection PubMed
description Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) reduces survival. In this study we hypothesized that methylation of key genes mediates cisplatin resistance. We determined whether a demethylating drug, decitabine, could augment the anti-proliferative and apoptotic effects of cisplatin on SCC-25/CP, a cisplatin-resistant tongue SCC cell line. We showed that decitabine treatment restored cisplatin sensitivity in SCC-25/CP and significantly reduced the cisplatin dose required to induce apoptosis. We then created a xenograft model with SCC-25/CP and determined that decitabine and cisplatin combination treatment resulted in significantly reduced tumor growth and mechanical allodynia compared to control. To establish a gene classifier we quantified methylation in cancer tissue of cisplatin-sensitive and cisplatin-resistant HNSCC patients. Cisplatin-sensitive and cisplatin-resistant patient tumors had distinct methylation profiles. When we quantified methylation and expression of genes in the classifier in HNSCC cells in vitro, we showed that decitabine treatment of cisplatin-resistant HNSCC cells reversed methylation and gene expression toward a cisplatin-sensitive profile. The study provides direct evidence that decitabine restores cisplatin sensitivity in in vitro and in vivo models of HNSCC. Combination treatment of cisplatin and decitabine significantly reduces HNSCC growth and HNSCC pain. Furthermore, gene methylation could be used as a biomarker of cisplatin-resistance.
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spelling pubmed-42292952014-11-18 Decitabine Rescues Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma Viet, Chi T. Dang, Dongmin Achdjian, Stacy Ye, Yi Katz, Samuel G. Schmidt, Brian L. PLoS One Research Article Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) reduces survival. In this study we hypothesized that methylation of key genes mediates cisplatin resistance. We determined whether a demethylating drug, decitabine, could augment the anti-proliferative and apoptotic effects of cisplatin on SCC-25/CP, a cisplatin-resistant tongue SCC cell line. We showed that decitabine treatment restored cisplatin sensitivity in SCC-25/CP and significantly reduced the cisplatin dose required to induce apoptosis. We then created a xenograft model with SCC-25/CP and determined that decitabine and cisplatin combination treatment resulted in significantly reduced tumor growth and mechanical allodynia compared to control. To establish a gene classifier we quantified methylation in cancer tissue of cisplatin-sensitive and cisplatin-resistant HNSCC patients. Cisplatin-sensitive and cisplatin-resistant patient tumors had distinct methylation profiles. When we quantified methylation and expression of genes in the classifier in HNSCC cells in vitro, we showed that decitabine treatment of cisplatin-resistant HNSCC cells reversed methylation and gene expression toward a cisplatin-sensitive profile. The study provides direct evidence that decitabine restores cisplatin sensitivity in in vitro and in vivo models of HNSCC. Combination treatment of cisplatin and decitabine significantly reduces HNSCC growth and HNSCC pain. Furthermore, gene methylation could be used as a biomarker of cisplatin-resistance. Public Library of Science 2014-11-12 /pmc/articles/PMC4229295/ /pubmed/25391133 http://dx.doi.org/10.1371/journal.pone.0112880 Text en © 2014 Viet et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Viet, Chi T.
Dang, Dongmin
Achdjian, Stacy
Ye, Yi
Katz, Samuel G.
Schmidt, Brian L.
Decitabine Rescues Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma
title Decitabine Rescues Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma
title_full Decitabine Rescues Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma
title_fullStr Decitabine Rescues Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma
title_full_unstemmed Decitabine Rescues Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma
title_short Decitabine Rescues Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma
title_sort decitabine rescues cisplatin resistance in head and neck squamous cell carcinoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229295/
https://www.ncbi.nlm.nih.gov/pubmed/25391133
http://dx.doi.org/10.1371/journal.pone.0112880
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