Benzyl Isothiocyanate Pretreatment Enhances Chemoradiation Response in HPV-Negative Head and Neck Squamous Cell Carcinoma
4 affiliations
- 1Department of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA
- 2Department of Otolaryngology-Head & Neck Surgery, University of Mississippi Medical Center, Jackson, MS 39216, USA
- 3Department of Radiation Oncology, School of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
- 4Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
Abstract
Head and neck squamous cell carcinoma (HNSCC) accounts for ~3% of U.S. cancer diagnoses, and many patients present with locally or regionally advanced disease. Despite multimodal standard-of-care (SOC) treatment, the median overall survival for recurrent or metastatic disease remains ~12 months. Acquired resistance to cisplatin (CDDP) and radiotherapy (RT) remains a central barrier to durable response, motivating neoadjuvant strategies to improve efficacy in resistant tumors. Benzyl isothiocyanate (BITC) is a dietary phytochemical with selective anticancer activity. Across four patient-matched HNSCC cell lines spanning a range of intrinsic sensitivities to CDDP or RT, pretreatment with BITC before RT and CDDP significantly increased HNSCC cell death as measured by caspase-3/7 activity, regardless of each cell line’s single-agent sensitivity. Within 24 h, BITC elevated cytoplasmic ROS across all lines: BITC-resistant cell lines countered this with a more robust increase in the GSH/GSSG ratio and retained viability, whereas the BITC-sensitive lines mounted a weaker glutathione (GSH) response and required rescue with exogenous GSH or N-acetylcysteine (NAC), indicating redox-sensitive cytotoxicity. Transcriptomic time-course analysis suggested that BITC induces a coordinated stress response, including proteotoxic HSF1 activation, and suppresses DNA replication and homologous recombination repair, thereby supporting a transcriptional basis for the observed sensitization to DNA-damaging therapy. By enhancing the efficacy of RT and CDDP in HPV-negative HNSCC, BITC may be a promising neoadjuvant strategy to improve the therapeutic index of chemotherapy and radiation in these patients, warranting further investigation.
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BibTeX
@article{kirven2026benzyl,
title = {{Benzyl Isothiocyanate Pretreatment Enhances Chemoradiation Response in HPV-Negative Head and Neck Squamous Cell Carcinoma}},
author = {Imani A. Kirven and Patrice Penfornis and Linda L. Eastham and Gina D. Jefferson and Chunli Yang and William N. Duggar and Rojymon Jacob and Lorenzo Lo Muzio and Pier Paolo Claudio},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219990},
url = {https://www.mdpi.com/1422-0067/27/21/9990},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Benzyl Isothiocyanate Pretreatment Enhances Chemoradiation Response in HPV-Negative Head and Neck Squamous Cell Carcinoma
AU - Imani A. Kirven
AU - Patrice Penfornis
AU - Linda L. Eastham
AU - Gina D. Jefferson
AU - Chunli Yang
AU - William N. Duggar
AU - Rojymon Jacob
AU - Lorenzo Lo Muzio
AU - Pier Paolo Claudio
PY - 2026
DA - 2026/11/07
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219990
UR - https://www.mdpi.com/1422-0067/27/21/9990
AB - Head and neck squamous cell carcinoma (HNSCC) accounts for ~3% of U.S. cancer diagnoses, and many patients present with locally or regionally advanced disease. Despite multimodal standard-of-care (SOC) treatment, the median overall survival for recurrent or metastatic disease remains ~12 months. Acquired resistance to cisplatin (CDDP) and radiotherapy (RT) remains a central barrier to durable response, motivating neoadjuvant strategies to improve efficacy in resistant tumors. Benzyl isothiocyanate (BITC) is a dietary phytochemical with selective anticancer activity. Across four patient-matched HNSCC cell lines spanning a range of intrinsic sensitivities to CDDP or RT, pretreatment with BITC before RT and CDDP significantly increased HNSCC cell death as measured by caspase-3/7 activity, regardless of each cell line’s single-agent sensitivity. Within 24 h, BITC elevated cytoplasmic ROS across all lines: BITC-resistant cell lines countered this with a more robust increase in the GSH/GSSG ratio and retained viability, whereas the BITC-sensitive lines mounted a weaker glutathione (GSH) response and required rescue with exogenous GSH or N-acetylcysteine (NAC), indicating redox-sensitive cytotoxicity. Transcriptomic time-course analysis suggested that BITC induces a coordinated stress response, including proteotoxic HSF1 activation, and suppresses DNA replication and homologous recombination repair, thereby supporting a transcriptional basis for the observed sensitization to DNA-damaging therapy. By enhancing the efficacy of RT and CDDP in HPV-negative HNSCC, BITC may be a promising neoadjuvant strategy to improve the therapeutic index of chemotherapy and radiation in these patients, warranting further investigation.
SN - 1422-0067
ER -