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

Solovieva, Marina E.; Shatalin, Yuri V.; Фадеев, Р. С.; Krestinina, Olga; Baburina, Yulia; Kruglov, Alexey G.; Kharechkina, Ekaterina S.; Kobyakova, M. I.; Rogachevsky, Vadim; Shishkova, E. A.; Akatov, And Vladimir

doi:10.3390/biom10010069

Cited by 16 publications

(20 citation statements)

References 57 publications

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“…Probably, ROS formed during the oxidation of DDC rapidly transform to reactive sulfur species. This could explain a partial inhibition of the cytotoxic effect of the combination of DDC with H2OCbl + /HOCbl by catalase, which was observed here and earlier [39,51]. The absence of any influence of CNCbl on the DDC-induced cell death as well as the absence of CL during the oxidation of DDC in the presence of CNCbl may be due to a slow oxidation of this compound.…”

Section: Discussionsupporting

confidence: 73%

“…Our previous results have indicated that combinations of HOCbl with GSH, NAC, AA [31], DTT [32], and DDC [38,39,51] produce a cytotoxic effect on HEp-2 cells. It was shown using an oxygen electrode that the oxidation of thiols [31,32] and AA [31] catalyzed by H2OCbl + /HOCbl is accompanied by the accumulation of hydrogen peroxide in culture medium.…”

Section: Discussionmentioning

confidence: 96%

“…Our previous results indicate that combinations of HOCbl with GSH, NAC, DTT, and АА lead to apoptotic death in cancer cells [31,32,37]. At the same time, a combination of HOCbl with DDC leads to entosis [38] and/or paraptosis-like cell death [38,39]. For a more complete understanding of mechanisms underlying the effects of cobalamin-reducing agent combinations, first of all a deeper insight into ongoing chemical processes is needed.…”

Section: Introductionmentioning

confidence: 99%

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A Comparative Study of ROS Production and Cytotoxicity Induced by Combinations of Thiols with HOCbl and CNCbl

Shatalin¹,

Shubina²,

Solovieva³

et al. 2022

Preprint

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Cobalamin is an essential nutrient required for the normal functioning of cells. Its deficiency can lead to various pathological states. Hydroxocobalamin (HOCbl) and cyanocobalamin (CNCbl) are the forms of vitamin B12 that are most commonly used for supplementation. There is substantial evidence indicating that cobalamins can both suppress and promote oxidative stress; however, the mechanisms underlying these effects are poorly understood. Here, it was shown that the oxidation of thiols catalyzed by HOCbl and CNCbl is accompanied by ROS production and induces, under certain conditions, oxidative stress and cell death. The form of vitamin B12 and the structure of thiol play a decisive role in these processes. It was found that the mechanisms and kinetics of thiol oxidation catalyzed by HOCbl and CNCbl differ substantially. It was discussed how these differences may explain different levels of ROS production and cytotoxicity induced by combinations of thiols with HOCbl and CNCbl. On the whole, the data obtained provide a new insight into the redox processes in which cobalamins are involved and might be helpful in developing new approaches to the treatment of some cobalamin-responsive disorders in which oxidative stress is an important component. In addition, these data may be useful for a better understanding of mechanisms underlying induction of different types of death of cancer cells and in a search for new targets for anticancer therapy.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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A Comparative Study of ROS Production and Cytotoxicity Induced by Combinations of Thiols with HOCbl and CNCbl

Shatalin¹,

Shubina²,

Solovieva³

et al. 2022

Preprint

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“…Additionally, it was shown that vitamin B12 contributes to a distinctive mechanism of cell death known as paraptosis-like cell death. The combination of vitamin B12 with diethyldithiocarbamate stimulated disulfiram oxiderivatives formation resulting in severe ER stress and extensive ER vacuolization leading to paraptosis-like cell death [35]. Moreover, a study done on HL-60 human lymphocytic leukemia cell line showed that the use of vitamin B12 in combination with thiol antioxidants such as dithiothreitol (DTT), glutathione, and N-acetylcysteine resulted in lysosome dysfunction followed by apoptosis [36].…”

Section: Introductionmentioning

confidence: 99%

Vitamin B12 enhances the antitumor activity of 1,25-dihydroxyvitamin D3 via activation of caspases and targeting actin cytoskeleton

Atoum

Alzoughool

Al-Mazaydeh

et al. 2022

TUB

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BACKGROUND: 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is an effective anticancer agent, and when combined with other agents it shows superior activities. Vitamin B12 has been shown to contribute to increasing the effectiveness of anticancer drugs when used in combination. Thus, the current study aimed at investigating the anticancer potential of the combination of 1,25(OH)2D3 and vitamin B12. METHODS: MTT assay was used to determine the cytotoxic activity of combining 1,25(OH)2D3 and vitamin B12 against six different cancer cell lines and one normal cell line. The surviving fraction after clonogenic assay was measured, and the effects of 1,25(OH)2D3/B12 combination on the activity of different caspases, cell adhesion, actin cytoskeleton, cell morphology, and percentage of polarized cells were evaluated. RESULTS: Vitamin B12 did not cause cytotoxicity, however, it enhanced the cytotoxicity of 1,25(OH)2D3 against cancer cells. The cytotoxic effects of 1,25(OH)2D3 and its combination with vitamin B12 was not evident in the normal mammary MCF10A cell line indicating cancer cell-specificity. The cytotoxic effects of 1,25(OH)2D3/B12 combination occurred in a dose-dependent manner and was attributed to apoptosis induction which was mediated by caspase 4 and 8. Moreover, 1,25(OH)2D3/B12-treated cells showed enhanced inhibition of clonogenic tumor growth, reduced cell adhesion, reduced cell area, reduced percentage of cell polarization, and disorganized actin cytoskeleton resulting in reduced migratory phenotype when compared to cells treated with 1,25(OH)2D3 alone. CONCLUSION: 1,25(OH)2D3 and vitamin B12 exhibited synergistic anticancer effects against different cancer cell lines. The combination therapy of 1,25(OH)2D3 and vitamin B12 may provide a potential adjunctive treatment option for some cancer types.

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“…Our previous results indicate that combinations of HOCbl with GSH, NAC, DTT, and ascorbic acid (AA) lead to apoptotic death in cancer cells [ 31 , 32 , 37 ]. At the same time, a combination of HOCbl with sodium diethyldithiocarbamate (DDC) leads to entosis [ 38 ] and/or paraptosis-like cell death [ 38 , 39 ]. For a more complete understanding of mechanisms underlying the effects of cobalamin-reducing agent combinations, a deeper insight into ongoing chemical processes is needed.…”

Section: Introductionmentioning

confidence: 99%

Differences in the Formation of Reactive Oxygen Species and Their Cytotoxicity between Thiols Combined with Aqua- and Cyanocobalamins

Shatalin

Shubina

Solovieva

et al. 2022

IJMS

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Cobalamin is an essential nutrient required for the normal functioning of cells. Its deficiency can lead to various pathological states. Hydroxocobalamin (HOCbl) and cyanocobalamin (CNCbl) are the forms of vitamin B12 that are most commonly used for supplementation. There is substantial evidence indicating that cobalamins can both suppress and promote oxidative stress; however, the mechanisms underlying these effects are poorly understood. Here, it was shown that the oxidation of thiols catalyzed by HOCbl and CNCbl is accompanied by reactive oxygen species (ROS) production and induces, under certain conditions, oxidative stress and cell death. The form of vitamin B12 and the structure of thiol play a decisive role in these processes. It was found that the mechanisms and kinetics of thiol oxidation catalyzed by HOCbl and CNCbl differ substantially. HOCbl increased the rate of oxidation of thiols to a greater extent than CNCbl, but quenched ROS in combination with certain thiols. Oxidation catalyzed by CNCbl was generally slower. Yet, the absence of ROS quenching resulted in their higher accumulation. The aforementioned results might explain a more pronounced cytotoxicity induced by combinations of thiols with CNCbl. On the whole, the data obtained provide a new insight into the redox processes in which cobalamins are involved. Our results might also be helpful in developing new approaches to the treatment of some cobalamin-responsive disorders in which oxidative stress is an important component.

show abstract

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

Cited by 16 publications

References 57 publications

A Comparative Study of ROS Production and Cytotoxicity Induced by Combinations of Thiols with HOCbl and CNCbl

A Comparative Study of ROS Production and Cytotoxicity Induced by Combinations of Thiols with HOCbl and CNCbl

Vitamin B12 enhances the antitumor activity of 1,25-dihydroxyvitamin D3 via activation of caspases and targeting actin cytoskeleton

Differences in the Formation of Reactive Oxygen Species and Their Cytotoxicity between Thiols Combined with Aqua- and Cyanocobalamins

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