Cytotoxic effects of vitamins K1, K2, and K3 against human T lymphoblastoid leukemia cells through apoptosis induction and cell cycle arrest

Xu, Wen‐Cheng; Wu, Huijun; Chen, Shuhe; Wang, Xiaoqin; Tanaka, Sachiko; Sugiyama, Kentaro; Yamada, Hideaki; Hirano, Toshihiko

doi:10.1111/cbdd.13696

Cited by 8 publications

(5 citation statements)

References 33 publications

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“…Other mechanisms of VK2-induced leukemic cell apoptosis and differentiation include upregulation of p27 protein expression [ 147 ], disruption of mitochondrial membrane potential by VK2-Bcl antagonist killer 1 (Bak) binding [ 151 ], cleavage of PARP and down-regulation of cyclin A2 expression [ 152 ]. VK2-initiated mitochondrial apoptosis and ROS generation pathways were also observed in cultured studies of myeloma cells [ 153 ] and human ovarian cancer TYK-nu cells [ 154 ].…”

Section: Potential Therapeutic Benefitsmentioning

confidence: 99%

Vitamin K2 in Health and Disease: A Clinical Perspective

Zhang,

O’Connor,

Sheridan

et al. 2024

Foods

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Vitamins are essential organic compounds that vary widely in chemical structure and are vital in small quantities for numerous biochemical and biological functions. They are critical for metabolism, growth, development and maintaining overall health. Vitamins are categorised into two groups: hydrophilic and lipophilic. Vitamin K (VK), a lipophilic vitamin, occurs naturally in two primary forms: phylloquinone (VK1), found in green leafy vegetables and algae, and Menaquinones (VK2), present in certain fermented and animal foods and widely formulated in VK supplements. This review explores the possible factors contributing to VK deficiency, including dietary influences, and discusses the pharmacological and therapeutic potential of supplementary VK2, examining recent global clinical studies on its role in treating diseases such as osteoporosis, osteoarthritis, rheumatoid arthritis, cardiovascular disease, chronic kidney disease, diabetes, neurodegenerative disorders and cancers. The analysis includes a review of published articles from multiple databases, including Scopus, PubMed, Google Scholar, ISI Web of Science and CNKI, focusing on human studies. The findings indicate that VK2 is a versatile vitamin essential for human health and that a broadly positive correlation exists between VK2 supplementation and improved health outcomes. However, clinical data are somewhat inconsistent, highlighting the need for further detailed research into VK2′s metabolic processes, biomarker validation, dose–response relationships, bioavailability and safety. Establishing a Recommended Daily Intake for VK2 could significantly enhance global health.

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Section: Potential Therapeutic Benefitsmentioning

confidence: 99%

Vitamin K2 in Health and Disease: A Clinical Perspective

Zhang,

O’Connor,

Sheridan

et al. 2024

Foods

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“…It is interesting to note that the strong synergistic antiproliferative and cytotoxic effects on cancer cells are inherent for the combination of ascorbate with K3, but not for the combination of ascorbate with vitamins K1 or K2 [9]. K3 has also been found to be more effective than vitamins K1 and K2 when administered alone [9,32,33]. This suggests that prenylation of quinones abolishes their anticancer activity.…”

Section: Introductionmentioning

confidence: 99%

Redox-Cycling “Mitocans” as Effective New Developments in Anticancer Therapy

Bakalova

Lazarova

Sumiyoshi

et al. 2023

IJMS

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Our study proposes a pharmacological strategy to target cancerous mitochondria via redox-cycling “mitocans” such as quinone/ascorbate (Q/A) redox-pairs, which makes cancer cells fragile and sensitive without adverse effects on normal cells and tissues. Eleven Q/A redox-pairs were tested on cultured cells and cancer-bearing mice. The following parameters were analyzed: cell proliferation/viability, mitochondrial superoxide, steady-state ATP, tissue redox-state, tumor-associated NADH oxidase (tNOX) expression, tumor growth, and survival. Q/A redox-pairs containing unprenylated quinones exhibited strong dose-dependent antiproliferative and cytotoxic effects on cancer cells, accompanied by overproduction of mitochondrial superoxide and accelerated ATP depletion. In normal cells, the same redox-pairs did not significantly affect the viability and energy homeostasis, but induced mild mitochondrial oxidative stress, which is well tolerated. Benzoquinone/ascorbate redox-pairs were more effective than naphthoquinone/ascorbate, with coenzyme Q0/ascorbate exhibiting the most pronounced anticancer effects in vitro and in vivo. Targeted anticancer effects of Q/A redox-pairs and their tolerance to normal cells and tissues are attributed to: (i) downregulation of quinone prenylation in cancer, leading to increased mitochondrial production of semiquinone and, consequently, superoxide; (ii) specific and accelerated redox-cycling of unprenylated quinones and ascorbate mainly in the impaired cancerous mitochondria due to their redox imbalance; and (iii) downregulation of tNOX.

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“…Non-prenylated quinones appear to have greater potential as anticancer agents than prenylated ones. For example, menadione has been found to be more effective than vitamins K1 and K2 [ 4 , 16 , 17 ]. Synergistic antiproliferative and cytotoxic effects on cancer cells are inherent for the M/A combination, but not for the K1/A and K2/A combinations [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Tolerable treatment of glioblastoma with redox-cycling ‘mitocans': a comparative study in vivo

et al. 2023

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Objectives: The present study describes a pharmacological strategy for the treatment of glioblastoma by redoxcycling ‘mitocans’ such as quinone/ascorbate combination drugs, based on their tumor-selective redox-modulating effects and tolerance to normal cells and tissues. Methods: Experiments were performed on glioblastoma mice (orthotopic model) treated with coenzyme Q0/ascorbate (Q0/A). The drug was injected intracranially in a single dose. The following parameters were analyzed in vivo using MRI orex vivo using conventional assays: tumor growth, survival, cerebral and tumor perfusion, tumor cell density, tissue redox-state, and expression of tumor-associated NADH oxidase (tNOX). Results: Q0/A markedly suppressed tumor growth and significantly increased survival of glioblastoma mice. This was accompanied by increased oxidative stress in the tumor but not in non-cancerous tissues, increased tumor blood flow, and downregulation of tNOX. The redox-modulating and anticancer effects of Q0/A were more pronounced than those of menadione/ascorbate (M/A) obtained in our previous study. No adverse drug-related side-effects were observed in glioblastoma mice treated with Q0/A. Discussion: Q0/A differentiated cancer cells and tissues, particularly glioblastoma, from normal ones by redox targeting, causing a severe oxidative stress in the tumor but not in non-cancerous tissues. Q0/A had a pronounced anticancer activity and could be considered safe for the organism within certain concentration limits. The results suggest that the rate of tumor resorption and metabolism of toxic residues must be controlled and maintained within tolerable limits to achieve longer survival, especially at intracranial drug administration.

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Cytotoxic effects of vitamins K1, K2, and K3 against human T lymphoblastoid leukemia cells through apoptosis induction and cell cycle arrest

Cited by 8 publications

References 33 publications

Vitamin K2 in Health and Disease: A Clinical Perspective

Vitamin K2 in Health and Disease: A Clinical Perspective

Redox-Cycling “Mitocans” as Effective New Developments in Anticancer Therapy

Tolerable treatment of glioblastoma with redox-cycling ‘mitocans': a comparative study in vivo

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