{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:24:56Z","timestamp":1790825096290,"version":"4.1.0"},"reference-count":70,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,5,6]],"date-time":"2019-05-06T00:00:00Z","timestamp":1557100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DE019678"],"award-info":[{"award-number":["DE019678"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK088227"],"award-info":[{"award-number":["DK088227"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["CA198103"],"award-info":[{"award-number":["CA198103"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Children's Hospital of Michigan Foundation","award":["none"],"award-info":[{"award-number":["none"]}]},{"name":"Am. Academy of Otolaryngology","award":["none"],"award-info":[{"award-number":["none"]}]},{"name":"Wayne State University Department of Otolaryngology","award":["none"],"award-info":[{"award-number":["none"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/jcm8050611","type":"journal-article","created":{"date-parts":[[2019,5,9]],"date-time":"2019-05-09T11:22:35Z","timestamp":1557400955000},"page":"611","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Disulfiram (Antabuse) Activates ROS-Dependent ER Stress and Apoptosis in Oral Cavity Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"8","author":[{"given":"Priyanka","family":"Shah O\u2019Brien","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Xi","sequence":"additional","affiliation":[{"name":"Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin R.","family":"Miller","sequence":"additional","affiliation":[{"name":"Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy L.","family":"Brownell","sequence":"additional","affiliation":[{"name":"Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghua","family":"Zeng","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George H.","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle M.","family":"Garshott","sequence":"additional","affiliation":[{"name":"Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew B.","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Henry Ford Hospital, Diagnostic Radiology Residency, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony E.","family":"Galinato","sequence":"additional","affiliation":[{"name":"Henry Ford Hospital, Diagnostic Radiology Residency, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Cai","sequence":"additional","affiliation":[{"name":"Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Narula","sequence":"additional","affiliation":[{"name":"Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael U.","family":"Callaghan","sequence":"additional","affiliation":[{"name":"Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4277-316X","authenticated-orcid":false,"given":"Randal J.","family":"Kaufman","sequence":"additional","affiliation":[{"name":"Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M.","family":"Fribley","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Division of Hematology\/Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"},{"name":"Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,6]]},"reference":[{"key":"ref_1","unstructured":"(2019, March 27). Oral Cancer Foundation. Available online: https:\/\/oralcancerfoundation.org\/facts\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/S1368-8375(97)00029-8","article-title":"Epidemiology and prevention of oral cancer","volume":"33","author":"Tavani","year":"1997","journal-title":"Oral Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/S1368-8375(98)00022-0","article-title":"Possible mechanisms by which alcohol may influence the development of oral cancer--a review","volume":"34","author":"Wight","year":"1998","journal-title":"Oral Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S0266-4356(98)90707-0","article-title":"Aetiology of oral cancer: Alcohol","volume":"36","author":"Ogden","year":"1998","journal-title":"Br. J. Oral Maxillofac. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1080\/21505594.2014.999570","article-title":"HPV and cancer of the oral cavity","volume":"6","author":"Hubbers","year":"2015","journal-title":"Virulence"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"458","DOI":"10.4103\/0973-1482.186696","article-title":"Oral cancer: Etiology and risk factors: A review","volume":"12","author":"Kumar","year":"2016","journal-title":"J. Cancer Res. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ramsey, T., Hojjat, H., Yuhan, B., Svider, P.F., Eloy, J.A., Folbe, A.J., Raza, S.N., and Fribley, A.M. (2019). Disparities in impact of nasopharyngeal cancer: An analysis of global health burden. Laryngoscope.","DOI":"10.1002\/lary.27532"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1002\/lary.27068","article-title":"Laryngeal cancer: Global socioeconomic trends in disease burden and smoking habits","volume":"128","author":"Ramsey","year":"2018","journal-title":"Laryngoscope"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1021\/acsmedchemlett.5b00133","article-title":"Borrelidin Induces the Unfolded Protein Response in Oral Cancer Cells and Chop-Dependent Apoptosis","volume":"6","author":"Sidhu","year":"2015","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1021\/ml5003234","article-title":"Discovery of Sulfonamidebenzamides as Selective Apoptotic CHOP Pathway Activators of the Unfolded Protein Response","volume":"5","author":"Flaherty","year":"2014","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1177\/0022034514559376","article-title":"Cantharidins induce ER stress and a terminal unfolded protein response in OSCC","volume":"94","author":"Xi","year":"2015","journal-title":"J. Dent. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8992","DOI":"10.1128\/MCB.23.24.8992-9002.2003","article-title":"Aberrant eukaryotic translation initiation factor 4E-dependent mRNA transport impedes hematopoietic differentiation and contributes to leukemogenesis","volume":"23","author":"Topisirovic","year":"2003","journal-title":"Mol. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1182\/blood-2009-02-205153","article-title":"Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): A proof-of-principle clinical trial with ribavirin","volume":"114","author":"Assouline","year":"2009","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1038\/sj.onc.1202563","article-title":"Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis","volume":"18","author":"Rosenwald","year":"1999","journal-title":"Oncogene"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/ijc.2910640107","article-title":"The proto-oncogene\/translation factor eIF4E: A survey of its expression in breast carcinomas","volume":"64","author":"Kerekatte","year":"1995","journal-title":"Int. J. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1001\/archotol.125.2.177","article-title":"Detection of the proto-oncogene eIF4E in larynx and hypopharynx cancers","volume":"125","author":"Franklin","year":"1999","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/sj.onc.1201216","article-title":"Detection of the proto-oncogene eIF4E in surgical margins may predict recurrence in head and neck cancer","volume":"15","author":"Nathan","year":"1997","journal-title":"Oncogene"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1172\/JCI0216886","article-title":"Orchestrating the unfolded protein response in health and disease","volume":"110","author":"Kaufman","year":"2002","journal-title":"J. Clin. Invest."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.cell.2009.01.042","article-title":"Regulation of translation initiation in eukaryotes: Mechanisms and biological targets","volume":"136","author":"Sonenberg","year":"2009","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3787","DOI":"10.1091\/mbc.10.11.3787","article-title":"Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress","volume":"10","author":"Haze","year":"1999","journal-title":"Mol. Biol. Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e43036","DOI":"10.7554\/eLife.43036","article-title":"The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1","volume":"7","author":"Li","year":"2018","journal-title":"Elife"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"33741","DOI":"10.1074\/jbc.273.50.33741","article-title":"Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors","volume":"273","author":"Yoshida","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1101\/gad.14.2.152","article-title":"An essential role in liver development for transcription factor XBP-1","volume":"14","author":"Reimold","year":"2000","journal-title":"Genes Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/ncb2738","article-title":"ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death","volume":"15","author":"Han","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1177\/1087057111414893","article-title":"Complementary cell-based high-throughput screens identify novel modulators of the unfolded protein response","volume":"16","author":"Fribley","year":"2011","journal-title":"J. Biomol. Screen"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/j.1600-0447.1992.tb03310.x","article-title":"A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites","volume":"369","author":"Johansson","year":"1992","journal-title":"Acta. Psychiatr. Scand. Suppl."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"13748","DOI":"10.1021\/bi970948e","article-title":"Inhibition of recombinant human mitochondrial and cytosolic aldehyde dehydrogenases by two candidates for the active metabolites of disulfiram","volume":"36","author":"Lam","year":"1997","journal-title":"Biochemistry"},{"key":"ref_28","first-page":"3074","article-title":"Modification of the sensitivity and repair of potentially lethal damage by diethyldithiocarbamate during and following exposure of plateau-phase cultures of mammalian cells to radiation and cis-diamminedichloroplatinum(II)","volume":"42","author":"Evans","year":"1982","journal-title":"Cancer Res."},{"key":"ref_29","first-page":"4490","article-title":"Effect of disulfiram (tetraethylthiuram disulfide) amd diethyldithiocarbamate on the bladder toxicity and antitumor activity of cyclophosphamide in mice","volume":"42","author":"Hacker","year":"1982","journal-title":"Cancer Res."},{"key":"ref_30","first-page":"2751","article-title":"Selective protection against cis-diamminedichloroplatinum(II)-induced toxicity in kidney, gut, and bone marrow by diethyldithiocarbamate","volume":"46","author":"Bodenner","year":"1986","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1038\/bjc.2011.126","article-title":"Disulfiram modulated ROS-MAPK and NFkappaB pathways and targeted breast cancer cells with cancer stem cell-like properties","volume":"104","author":"Yip","year":"2011","journal-title":"Br. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9695","DOI":"10.1128\/MCB.24.22.9695-9704.2004","article-title":"Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells","volume":"24","author":"Fribley","year":"2004","journal-title":"Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein measurement with the Folin phenol reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/B978-0-12-385928-0.00004-3","article-title":"Large-scale analysis of UPR-mediated apoptosis in human cells","volume":"491","author":"Fribley","year":"2011","journal-title":"Methods Enzymol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/978-1-60327-017-5_14","article-title":"Regulation of apoptosis by the unfolded protein response","volume":"559","author":"Fribley","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"ref_36","first-page":"1269","article-title":"Resveratrol induces pro-apoptotic endoplasmic reticulum stress in human colon cancer cells","volume":"18","author":"Park","year":"2007","journal-title":"Oncol. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6235","DOI":"10.1021\/ja109413c","article-title":"Copper binding agents acting as copper ionophores lead to caspase inhibition and paraptotic cell death in human cancer cells","volume":"133","author":"Tardito","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"645","DOI":"10.3382\/ps.0660645","article-title":"Effects of light source, ambient temperature, and dietary energy source on the general performance and incidence of leg abnormalities of roaster chickens","volume":"66","author":"Hulan","year":"1987","journal-title":"Poult. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1016\/S1097-2765(01)00265-9","article-title":"Translational control is required for the unfolded protein response and in vivo glucose homeostasis","volume":"7","author":"Scheuner","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1016\/S0021-9258(18)52199-2","article-title":"Metal-catalyzed oxidation of proteins. Physiological consequences","volume":"266","author":"Stadtman","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_41","first-page":"2","article-title":"Effects of alcohol on workers with carbon disulfide","volume":"109","author":"Williams","year":"1937","journal-title":"JAMA"},{"key":"ref_42","first-page":"4","article-title":"A drug sensitizing the organism to ethyl alcohol","volume":"25","author":"Hald","year":"1948","journal-title":"Lancet"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/S0140-6736(48)91515-3","article-title":"Treatment of alcoholism with a sensitising drug","volume":"252","author":"Copenhagen","year":"1948","journal-title":"Lancet"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1093\/carcin\/bgt366","article-title":"Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage","volume":"35","author":"Paranjpe","year":"2014","journal-title":"Carcinogenesis"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.18632\/oncotarget.604","article-title":"Disulfiram, a drug widely used to control alcoholism, suppresses the self-renewal of glioblastoma and over-rides resistance to temozolomide","volume":"3","author":"Triscott","year":"2012","journal-title":"Oncotarget"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Chiba, T., Suzuki, E., Yuki, K., Zen, Y., Oshima, M., Miyagi, S., Saraya, A., Koide, S., Motoyama, T., and Ogasawara, S. (2014). Disulfiram eradicates tumor-initiating hepatocellular carcinoma cells in ROS-p38 MAPK pathway-dependent and -independent manners. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0084807"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2796","DOI":"10.18632\/oncotarget.6425","article-title":"Two clinical drugs deubiquitinase inhibitor auranofin and aldehyde dehydrogenase inhibitor disulfiram trigger synergistic anti-tumor effects in vitro and in vivo","volume":"7","author":"Huang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1158\/1535-7163.1049.3.9","article-title":"Disulfiram inhibits activating transcription factor\/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease","volume":"3","author":"Brar","year":"2004","journal-title":"Mol. Cancer Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/pros.21247","article-title":"Disulfiram is a DNA demethylating agent and inhibits prostate cancer cell growth","volume":"71","author":"Lin","year":"2011","journal-title":"Prostate"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.taap.2013.09.009","article-title":"A binuclear complex constituted by diethyldithiocarbamate and copper(I) functions as a proteasome activity inhibitor in pancreatic cancer cultures and xenografts","volume":"273","author":"Han","year":"2013","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.bcmd.2011.08.004","article-title":"Disulfiram\/copper complex activated JNK\/c-jun pathway and sensitized cytotoxicity of doxorubicin in doxorubicin resistant leukemia HL60 cells","volume":"47","author":"Xu","year":"2011","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e2797","DOI":"10.1038\/cddis.2017.176","article-title":"Disulfiram\/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-kappaB and Nrf2","volume":"8","author":"Xu","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"10425","DOI":"10.1158\/0008-5472.CAN-06-2126","article-title":"Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity","volume":"66","author":"Chen","year":"2006","journal-title":"Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"7471","DOI":"10.18632\/oncotarget.2166","article-title":"Liposome encapsulated Disulfiram inhibits NFkappaB pathway and targets breast cancer stem cells in vitro and in vivo","volume":"5","author":"Liu","year":"2014","journal-title":"Oncotarget"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Cheriyan, V.T., Wang, Y., Muthu, M., Jamal, S., Chen, D., Yang, H., Polin, L.A., Tarca, A.L., Pass, H.I., and Dou, Q.P. (2014). Disulfiram suppresses growth of the malignant pleural mesothelioma cells in part by inducing apoptosis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0093711"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1002\/jcb.25184","article-title":"Disulfiram\/copper-disulfiram Damages Multiple Protein Degradation and Turnover Pathways and Cytotoxicity is Enhanced by Metformin in Oesophageal Squamous Cell Carcinoma Cell Lines","volume":"116","author":"Jivan","year":"2015","journal-title":"J. Cell Biochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/35102167","article-title":"Stem cells, cancer, and cancer stem cells","volume":"414","author":"Reya","year":"2001","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1073\/pnas.0610117104","article-title":"Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma","volume":"104","author":"Prince","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1002\/hed.21315","article-title":"Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase","volume":"32","author":"Clay","year":"2010","journal-title":"Head Neck"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/hed.21699","article-title":"Frequency of cells expressing CD44, a head and neck cancer stem cell marker: Correlation with tumor aggressiveness","volume":"34","author":"Joshua","year":"2012","journal-title":"Head Neck"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1007\/s12015-018-9839-4","article-title":"Expression of Cancer Stem Cell Biomarkers in Human Head and Neck Carcinomas: A Systematic Review","volume":"14","author":"Curtarelli","year":"2018","journal-title":"Stem Cell Rev."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.bbrc.2009.05.048","article-title":"Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer","volume":"385","author":"Chen","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1002\/mc.22526","article-title":"Cancer stem cell mediated acquired chemoresistance in head and neck cancer can be abrogated by aldehyde dehydrogenase 1 A1 inhibition","volume":"56","author":"Kulsum","year":"2017","journal-title":"Mol. Carcinog."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.1002\/lary.22144","article-title":"Analysis of eIF4E and 4EBP1 mRNAs in head and neck cancer","volume":"121","author":"Palaniyandi","year":"2011","journal-title":"Laryngoscope"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Fribley, A.M. (2016). The Unfolded Protein Response as a Therapeutic Target for Head and Neck Squamous Cell Carcinoma. Targeting Oral Cancer, Springer International Publishing.","DOI":"10.1007\/978-3-319-27647-2"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1007\/s00018-009-8745-y","article-title":"Functions and pathologies of BiP and its interaction partners","volume":"66","author":"Dudek","year":"2009","journal-title":"Cell Mol. Life Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1158\/1078-0432.CCR-06-2082","article-title":"Reactive oxygen species: A breath of life or death?","volume":"13","author":"Fruehauf","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2006.10.029","article-title":"Dual role of hydrogen peroxide in cancer: Possible relevance to cancer chemoprevention and therapy","volume":"252","year":"2007","journal-title":"Cancer Lett."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"5557","DOI":"10.1074\/jbc.M210269200","article-title":"Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol","volume":"278","author":"Han","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1089\/ars.2007.1782","article-title":"Endoplasmic reticulum stress and oxidative stress: A vicious cycle or a double-edged sword?","volume":"9","author":"Malhotra","year":"2007","journal-title":"Antioxid. Redox. 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