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Disulfiram (Antabuse) Activates ROS-Dependent ER Stress and Apoptosis in Oral Cavity Squamous Cell Carcinoma.

ABSTRACT: A paucity of advances in the development of novel therapeutic agents for squamous cell carcinomas of the head and neck, oral cavity (OSCC) and oropharynx, has stagnated disease free survival rates over the past two decades. Although immunotherapies targeted against checkpoint inhibitors such as PD-1 or CTLA-4 are just now entering the clinic for late stage disease with regularity the median improvement in overall survival is only about three months. There is an urgent unmet clinical need to identify new therapies that can be used alone or in combination with current approaches to increase survival by more than a few months. Activation of the apoptotic arm of the unfolded response (UPR) with small molecules and natural products has recently been demonstrated to be a productive approach in pre-clinical models of OSCC and several other cancers. The aim of current study was to perform a high throughput screen (HTS) with a diverse chemical library to identify compounds that could induce CHOP, a component of the apoptotic arm of the UPR. Disulfiram (DSF, also known as Antabuse) the well-known aversion therapy used to treat chronic alcoholism emerged as a hit that could generate reactive oxygen species, activate the UPR and apoptosis and reduce proliferation in OSCC cell cultures and xenografts. A panel of murine embryonic fibroblasts null for key UPR intermediates (e.g., Chop and Atf4) was resistant to DSF suggesting that an intact UPR is a key element of the mechanism regulating the antiproliferative effects of DSF.

SUBMITTER: Shah O'Brien P

PROVIDER: S-EPMC6571807 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Disulfiram (Antabuse) Activates ROS-Dependent ER Stress and Apoptosis in Oral Cavity Squamous Cell Carcinoma.

Shah O'Brien Priyanka P Xi Yue Y Miller Justin R JR Brownell Amy L AL Zeng Qinghua Q Yoo George H GH Garshott Danielle M DM O'Brien Matthew B MB Galinato Anthony E AE Cai Peter P Narula Neha N Callaghan Michael U MU Kaufman Randal J RJ Fribley Andrew M AM

Journal of clinical medicine 20190506 5

A paucity of advances in the development of novel therapeutic agents for squamous cell carcinomas of the head and neck, oral cavity (OSCC) and oropharynx, has stagnated disease free survival rates over the past two decades. Although immunotherapies targeted against checkpoint inhibitors such as PD-1 or CTLA-4 are just now entering the clinic for late stage disease with regularity the median improvement in overall survival is only about three months. There is an urgent unmet clinical need to iden ...[more]

PMID: 31064122

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Project description:ImportanceOral cavity squamous cell carcinoma (SCC) tumors with mandibular invasion are upstaged to pT4a regardless of their size. Even small tumors with boney invasion, which would otherwise be classified as pT1-2, are recommended for the locally advanced treatment pathway to receive administration of postoperative radiotherapy (PORT).ObjectiveTo evaluate the association of PORT with overall survival according to tumor size among patients who received mandibulectomy for pT4aN0 oral cavity SCC.Design, setting, and participantsThis was a retrospective analysis using data from the US National Cancer Database from January 1, 2004, through December 31, 2019. All patients who received mandibulectomy for treatment-naive pT4aN0 oral cavity SCC with negative surgical margins were included. Data analyses were performed in January 2023 and finalized in July 2023.ExposurePORT vs no PORT.Main outcomes and measuresEntropy balancing was used to balance covariate moments between treatment groups. Weighted multivariable Cox proportional hazards regression was used to measure the association of PORT with overall survival associated with tumor size.ResultsAmong 3268 patients with pT4aN0 oral cavity SCC (mean [SD] age, 65.9 [12.1] years; 2024 [61.9%] male and 1244 [38.1%] female), 1851 (56.6%) received PORT and 1417 (43.4%) did not receive PORT. On multivariable analysis was adjusted for age, insurance status, Charlson Comorbidity Index score, tumor site, tumor grade, tumor size, and PORT. Findings indicated that PORT was associated with improved overall survival and that this relative survival advantage trended upwards with increasing tumor size. That is, the larger the tumor, the greater the survival advantage associated with the use of PORT. For the 1068 patients with tumors greater than 4 cm, the adjusted hazard ratio (aHR) in favor of PORT was 0.63 (95% CI, 0.48-0.82); for the 1774 patients with tumors greater than 2 cm but less than or equal to 4 cm, the aHR was 0.76 (95% CI, 0.62-0.93); and for 426 patients with tumors less than 2 cm, the aHR was 0.81 (95% CI, 0.57-1.15).Conclusions and relevanceIn this retrospective analysis of patients who received mandibulectomy for pT4aN0 oral cavity SCC, PORT was associated with improved overall survival, the benefit of which improved relatively with increasing tumor size. These findings suggest that tumor size should be considered in guidelines for PORT administration in this patient population.

Dataset Information

Disulfiram (Antabuse) Activates ROS-Dependent ER Stress and Apoptosis in Oral Cavity Squamous Cell Carcinoma.

Publications

Disulfiram (Antabuse) Activates ROS-Dependent ER Stress and Apoptosis in Oral Cavity Squamous Cell Carcinoma.

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