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Abstract
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.
Highlights
It is known that vitamin B12 is necessary for the metabolism of humans; it is used in the treatment of neurological, psychiatric, and toxicological diseases, as well as in anemia
As we have shown earlier, vitamin B12b enhanced the cytotoxic effect of DDC in subconfluent cultures of human A549, A431, HEp-2 cells [20]
We found a similar effect in human fibrosarcoma HT1080 and human colon adenocarcinoma HT29 cells (Figure 1a,b)
Summary
It is known that vitamin B12 is necessary for the metabolism of humans; it is used in the treatment of neurological, psychiatric, and toxicological diseases, as well as in anemia. Vitamins of group B12 participate as cofactors in hematopoiesis, the regulation of the metabolism of other vitamins, nitrous bases, amino acids, and fatty acids and affect gene expression [6,7]. There is evidence indicating that rapidly proliferating tumor cells and bacteria have increased demands for vitamin B12 which is due to the fact that cobalamin is a cofactor of 5-methyltetrahydrofolate-homocysteine methyl transferase, a key enzyme of the synthesis of deoxyribonucleotides [8]. Based on this evidence, studies devoted to possible application of B12 in antitumor therapy are being carried out.
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