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PLoS One. 2014 Nov 12;9(11):e112880. doi: 10.1371/journal.pone.0112880. eCollection 2014.

Decitabine rescues cisplatin resistance in head and neck squamous cell carcinoma.

Author information

1
Department of Oral Maxillofacial Surgery, New York University, New York, New York, United States of America; Bluestone Center for Clinical Research, New York University, New York, New York, United States of America.
2
Bluestone Center for Clinical Research, New York University, New York, New York, United States of America.

Abstract

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.

PMID:
25391133
PMCID:
PMC4229295
DOI:
10.1371/journal.pone.0112880
[Indexed for MEDLINE]
Free PMC Article

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