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

Chi T Viet,Stacy Achdjian,Dongmin Dang,Brian L Schmidt,Samuel G Katz,Yi Ye,Caterina Cinti

doi:10.1371/journal.pone.0112880

Chi T Viet, Stacy Achdjian + Show 5 more

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https://doi.org/10.1371/journal.pone.0112880

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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.

Highlights

More than 60% of head and neck squamous cell carcinoma (HNSCC) patients present with advanced-staged disease, which is associated with a high mortality rate [1]
Pre-treatment with decitabine restored the apoptotic activity of cisplatin on cisplatin-resistant cells, such that DACSCC-25/CP cells had significantly higher apoptotic activity than SCC-25/CP cells in response to cisplatin treatment
Decitabine pre-treatment enhanced the apoptotic effects of cisplatin on cisplatin-sensitive SCC-25 cells

Summary

Introduction

More than 60% of head and neck squamous cell carcinoma (HNSCC) patients present with advanced-staged disease, which is associated with a high mortality rate [1]. Cisplatin resistance occurs in some patients and significantly reduces survival as there are no effective alternative therapies. Aside from poor survival, HNSCC patients have significantly more pain than other cancer patients [6,7]. HNSCC-induced pain limits orofacial functions such as swallowing, mastication and speech, which results in poor quality of life. Outside of survival, pain-induced loss of function is the biggest concern for head and neck cancer patients [9,10]. Given the severe symptoms and reduced survival of HNSCC patients, a novel pharmacologic approach that both reduces cisplatin resistance and alleviates pain is needed

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