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

O’Brien, Priyanka Shah; Xi, Yue; Miller, Justin; Brownell, Amy L.; Zeng, Qinghua; Yoo, George H.; Garshott, Danielle M.; O'Brien, Matthew B.; Galinato, Anthony E.; Cai, Peter; Narula, Neha; Callaghan, Michael U.; Kaufman, Randal J.; Fribley, Andrew M.

doi:10.3390/jcm8050611

Cited by 32 publications

(24 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It follows from our results that ER stress is also induced in HEp-2 cells incubated in the presence of DDC alone, which is evidenced by the reversible vacuolization of the cytoplasm and the expression of ER markers. The capacity of DTC to induce ER stress was described in the literature [49,50]; however, there is evidence indicating that DDC is capable of diminishing the ER stress [51], and the DSF metabolite DETC-MeSO blocks the specific pathways of ER stress [52]. As seen from our data, cells in the presence of DDC or the classical ER stress inductor tunicamycin are able to survive despite the increased level of ER stress markers, in particular, BiP, IRE1, calnexin, and CHOP.…”

Section: Discussionmentioning

confidence: 99%

Vitamin B12b Enhances the Cytotoxicity of Diethyldithiocarbamate in a Synergistic Manner, Inducing the Paraptosis-Like Death of Human Larynx Carcinoma Cells

et al. 2020

View full text Add to dashboard Cite

We have shown that hydroxycobalamin (vitamin B12b) increases the toxicity of diethyldithiocarbamate (DDC) to tumor cells by catalyzing the formation of disulfiram (DSF) oxi-derivatives. The purpose of this study was to elucidate the mechanism of tumor cell death induced by the combination DDC + B12b. It was found that cell death induced by DDC + B12b differed from apoptosis, autophagy, and necrosis. During the initiation of cell death, numerous vacuoles formed from ER cisterns in the cytoplasm, and cell death was partially suppressed by the inhibitors of protein synthesis and folding, the IP3 receptor inhibitor as well as by thiols. At this time, a short-term rise in the expression of ER-stress markers BiP and PERK with a steady increase in the expression of CHOP were detected. After the vacuolization of the cytoplasm, functional disorders of mitochondria and an increase in the generation of superoxide anion in them occurred. Taken together, the results obtained indicate that DDC and B12b used in combination exert a synergistic toxic effect on tumor cells by causing severe ER stress, extensive ER vacuolization, and inhibition of apoptosis, which ultimately leads to the induction of paraptosis-like cell death.

show abstract

Section: Discussionmentioning

confidence: 99%

Vitamin B12b Enhances the Cytotoxicity of Diethyldithiocarbamate in a Synergistic Manner, Inducing the Paraptosis-Like Death of Human Larynx Carcinoma Cells

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Taken together, the tandem molecular self-assembly of Comp. 1 first disrupted the mitochondrial membrane, subsequently causing oxidative stress and increasing the levels of ROS, ultimately inducing the UPR, endoplasmic reticulum (ER) stress [41, 43, 44], and cell death.…”

Section: Resultsmentioning

confidence: 99%

Tandem Molecular Self-Assembly Selectively Inhibits Lung Cancer Cells by Inducing Endoplasmic Reticulum Stress

Zheng

Chen

et al. 2019

Research

View full text Add to dashboard Cite

The selective formation of nanomaterials in cancer cells and tumors holds great promise for cancer diagnostics and therapy. Until now, most strategies rely on a single trigger to control the formation of nanomaterials in situ. The combination of two or more triggers may provide for more sophisticated means of manipulation. In this study, we rationally designed a molecule (Comp. 1) capable of responding to two enzymes, alkaline phosphatase (ALP), and reductase. Since the A549 lung cancer cell line showed elevated levels of extracellular ALP and intracellular reductase, we demonstrated that Comp. 1 responded in a stepwise fashion to those two enzymes and displayed a tandem molecular self-assembly behavior. The selective formation of nanofibers in the mitochondria of the lung cancer cells led to the disruption of the mitochondrial membrane, resulting in an increased level of reactive oxygen species (ROS) and the release of cytochrome C (Cyt C). ROS can react with proteins, resulting in endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). This severe ER stress led to disruption of the ER, formation of vacuoles, and ultimately, apoptosis of the A549 cells. Therefore, Comp. 1 could selectively inhibit lung cancer cells in vitro and A549 xenograft tumors in vivo. Our study provides a novel strategy for the selective formation of nanomaterials in lung cancer cells, which is powerful and promising for the diagnosis and treatment of lung cancer.

show abstract

“…Disulfiram, an alcohol-abuse drug, was found to have anti-cancer activity and several mechanisms of its action were described [40]. Disulfiram triggered oxidative stress by the generation of reactive oxygene species and led to apoptosis in different cancer types [41,42,43]. This drug caused cell death by apoptosis via inhibition of the proteasome activity [44,45] and autophagic cell death was shown to be also one of its anti-cancer mechanisms [46,47].…”

Section: Discussionmentioning

confidence: 99%

Disulfiram Overcomes Cisplatin Resistance in Human Embryonal Carcinoma Cells

Schmidtova

Kalavska

Gercakova

et al. 2019

Cancers

View full text Add to dashboard Cite

Cisplatin resistance in testicular germ cell tumors (TGCTs) is a clinical challenge. We investigated the underlying mechanisms associated with cancer stem cell (CSC) markers and modalities circumventing the chemoresistance. Chemoresistant models (designated as CisR) of human embryonal carcinoma cell lines NTERA-2 and NCCIT were derived and characterized using flow cytometry, gene expression, functional and protein arrays. Tumorigenicity was determined on immunodeficient mouse model. Disulfiram was used to examine chemosensitization of resistant cells. ALDH1A3 isoform expression was evaluated by immunohistochemistry in 216 patients’ tissue samples. Chemoresistant cells were significantly more resistant to cisplatin, carboplatin and oxaliplatin compared to parental cells. NTERA-2 CisR cells exhibited altered morphology and increased tumorigenicity. High ALDH1A3 expression and increased ALDH activity were detected in both refractory cell lines. Disulfiram in combination with cisplatin showed synergy for NTERA-2 CisR and NCCIT CisR cells and inhibited growth of NTERA-2 CisR xenografts. Significantly higher ALDH1A3 expression was detected in TGCTs patients’ tissue samples compared to normal testicular tissue. We characterized novel clinically relevant model of chemoresistant TGCTs, for the first time identified the ALDH1A3 as a therapeutic target in TGCTs and more importantly, showed that disulfiram represents a viable treatment option for refractory TGCTs.

show abstract

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

Cited by 32 publications

References 69 publications

Vitamin B12b Enhances the Cytotoxicity of Diethyldithiocarbamate in a Synergistic Manner, Inducing the Paraptosis-Like Death of Human Larynx Carcinoma Cells

Vitamin B12b Enhances the Cytotoxicity of Diethyldithiocarbamate in a Synergistic Manner, Inducing the Paraptosis-Like Death of Human Larynx Carcinoma Cells

Tandem Molecular Self-Assembly Selectively Inhibits Lung Cancer Cells by Inducing Endoplasmic Reticulum Stress

Disulfiram Overcomes Cisplatin Resistance in Human Embryonal Carcinoma Cells

Contact Info

Product

Resources

About