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Biomolecules ; 10(1)2020 01 01.
Article in English | MEDLINE | ID: mdl-31906414

ABSTRACT

We have shown that hydroxycobalamin (vitamin В12b) 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 + В12b. 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.


Subject(s)
Ditiocarb/pharmacology , Hydroxocobalamin/pharmacology , Laryngeal Neoplasms/drug therapy , Apoptosis/drug effects , Autophagy/drug effects , Carcinoma/metabolism , Cell Death/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Ditiocarb/metabolism , Drug Synergism , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum Stress/drug effects , Humans , Hydroxocobalamin/metabolism , Laryngeal Neoplasms/metabolism , Larynx/metabolism , Mitochondria/metabolism , Oxidative Stress/drug effects , Vacuoles/drug effects , Vitamin B 12/metabolism , Vitamin B 12/pharmacology , Vitamins/metabolism , Vitamins/pharmacology
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