Anti-Cancer Properties of Vitamin K: Comparison
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Vitamin K is the common name for a group of compounds recognized as essential for blood clotting. The group comprises phylloquinone (K1)—a 2-methyl-3-phytyl-1,4-naphthoquinone; menaquinone (K2, MK)—a group of compounds with an unsaturated side chain in position 3 of a different number of isoprene units and a 1,4-naphthoquinone group and menadione (K3, MD)—a group of synthetic, water-soluble compounds 2-methyl-1,4-naphthoquinone. However, epidemiological studies suggest that vitamin K has various benefits that go beyond blood coagulation processes. A dietary intake of K1 is inversely associated with the risk of pancreatic cancer, K2 has the potential to induce a differentiation in leukemia cells or apoptosis of various types of cancer cells, and K3 has a documented anti-cancer effect. A healthy diet rich in fruit and vegetables ensures an optimal supply of K1 and K2, though consumers often prefer supplements. Interestingly, the synthetic form of vitamin K—menadione—appears in the cell during the metabolism of phylloquinone and is a precursor of MK-4, a form of vitamin K2 inaccessible in food.

  • vitamin K
  • anti-cancer
  • ROS

1. Introduction

Natural forms of vitamin K–K1 and K2—have only a low potential for toxicity. Therefore, the National Academy of Sciences and the European Food Safety Authority (EFSA) have not set an upper limit for vitamin K, which indicates that even a high supply will not cause any harmful effects to most people. However, K3 may demonstrate harmful potential: synthetic vitamin K3 can lead to liver damage and destruction of oxygen-carrying red blood cells [1][2]. Nevertheless, despite its harmful effect on humans, vitamin K3 has shown anti-cancer and anti-inflammatory properties in numerous studies. This may indicate that vitamin K has an important preventive role, especially K1, which is converted into menadione in the human intestinal cells [3], in the diet.

2. DNA Damage

Menadione, a product of phylloquinone metabolism, can participate in redox reactions and generates reactive oxygen species (ROS), which then leads to damage to DNA and other macromolecules. ROS production plays a primal and important role in menadione-mediated DNA damage. Quinones generate semiquinones by single-electron reactions or hydroquinones in the two-electron reaction [4]. The semiquinone (SQ) is a partially reduced free radical form (Q•−) that can be re-oxidized by molecular oxygen (O2 to generate O2−), so semiquinones can effectively contribute to the formation of superoxides in biological systems [5]. Like another quinone, doxorubicin, menadione exerts its cytotoxic effects by stimulating the generation of oxidative stress, leading to DNA damage [6].
Ngo et al. showed that when applied in cytotoxic doses, menadione induces the formation of ssDNA (SSB) and dsDNA (DSB) breaks in breast cancer cells (MCF-7) [6]. Researchers have shown that the number of DNA breaks is directly proportional to the concentration of menadione and is directly related to the level of ROS. Similar results were noted for the K562 line of chronic myeloid leukemia, where low concentrations of menadione resulted in an increase in the number of SSBs [7]. DNA breaks appeared as early as five minutes after exposure of cells to 15 µM menadione. Interestingly, damage repair was more impaired after incubating cells with menadione than with another quinone (2,3-dimethyl-1,4-naphthoquinone). The authors suggest that quinones induce cytostasis while maintaining the integrity of cell membranes. Low, non-toxic concentrations of menadione can generate DNA-damaging ROS in close proximity to DNA [8] in the presence of Fe2+; ssDNA breaks are a signal that activates the poly ADP ribose polymerase (PARP1) [9][10], which consumes the cellular NAD+ pool and activates the BER DNA repair process [7]. This results in metabolic exhaustion and a significant inhibition of cell proliferation.
ROS and the semiquinone radical generated during the one-electron reduction of menadione are reported as the major contributors to the DNA damage resulting from exposure to menadione. The intercalating mechanism of covalent binding of the semichinone radical to DNA was demonstrated after radioactive menadione incubation with DNA and measurements of covalently bound activity [4]. Intercalation to DNA by covalent binding of the semiquinone radical to nucleic acid has been observed for other quinone anti-cancer drugs such as adriamycin or daunorubicin [11]. Therefore, the ability of adriamycin to induce extensive chromosome aberration and increase the incidence of sister chromatid exchange is explained by its strong covalent bond to DNA. The semiquinone radical may take part in the formation of DNA strand breaks, although it is more often the result of the ROS generated in the one-electron reduction of menadione. A strong electrophilic radical initiates strand breakage through an electrophilic attack on the carbons of the deoxyribose backbone [12]. Menadione has been shown to induce DNA strand breaks in various cell types [13][14][15][16][17]. Free radicals resulting from one-electron reduction of menadione are also responsible for the depletion of GSH—preventing DNA binding of reactive metabolites of menadione [4].
Later studies on cardiomyocytes by Loor et al. confirmed the potential of menadione to produce rapid and significant oxidative stress in various subcellular compartments [9]. After an incubation of 25 min, menadione (25 µM) caused oxidation of RoGFP (the radiometric redox sensor), reaching 75% in the cytosol and 85% in the mitochondrial matrix; compared to the initial—reducing conditions, in the cytosol, RoGFP oxidation averaged from 20 to 30%. Moreover, during a four-hour incubation period, a decrease in the mitochondrial membrane potential was observed, reaching 39% of the initial value. Studies on PARP-1 -/- murine embryos confirmed that PARP1 activation is an important component of the menadione-induced death pathway. Subsequent tests conducted on the Fuchs’ corneal dystrophy (FECD) using menadione as oxidative stress in normal endothelial cell lines (HCERC-21T and HCECE) showed that menadione damages not only nuclear DNA (nDNA), but also mitochondrial DNA (mtDNA) [18]. Menadione induces various dysfunctions in MT, such as depolarization of the MT membrane, a change in organelle morphology, and at higher concentrations (50 and 100 μM) ATP depletion. After a six-hour incubation period, the release of cytochrome C into the cytosol and the cutting of procaspase nine and three were observed. These processes are accompanied by an increase in Ca2+ concentration in the cellular cytosol [19], which is an important secondary messenger in controlling cell death [20][21]. Menadione undergoes redox cycles, induces ROS generation, and repairs DNA without showing any carcinogenic potential [22]. In pancreatic acinar cells, it was observed that the application of 30 μM menadione triggered a marked and significant increase in ROS levels immediately after exposure to menadione [23]. Menadione generates acute ROS production and promotes the opening of permeability transition pores, and induces Ca2+ fluctuations in pancreatic acinar cells, thus promoting programmed cell death [19][23]. A similar mechanism of action is demonstrated by K2: treatment of K2 human ovarian cancer cells results in the production of peroxides and H2O2 and induction of apoptosis resulting from K2-mediated depolarization of mitochondrial membranes [24].
Highly mutagenic DNA damage is 8-oxo-2-deoxyguanosine (8-oxo-dG) considered as a marker of oxidative stress. 8-oxo-dG can mismatch with dA generating a G to T transversion. In the presence of ROS, guanine (G) is easily oxidized, making 8-oxo-2-deoxyguanine (8-oxoGua) the most abundant DNA damage [25][26][27][28][29][30]. In a study carried out on rat hepatocytes exposed to menadione, DNA breaks were observed, although no significant elevated levels of 8-oxo-dG were observed after the administration of 100 µM menadione (after 15 and 90 min) [31]. In other studies, using electron spin resonance (ESR) analysis, it was found that 100 µM menadione induced a significant increase in the amount of 8-oxo-dG in Caco-2 cells after two hours’ incubation [32]. Similarly, the incubation of human breast carcinoma cells in the presence of 25 or 50 μM menadione for one hour generated 8-oxo-dG in mtDNA, and higher concentrations (100 and 200 μM) resulted in DNA strand breakage [33]. Analysis of gene expression as a result of treatment of Caco-2 menadion cells found 979 genes to demonstrate altered expression, and menadione modulated a number of significant processes including the transcription and regulation of the cell cycle, glutathione metabolism, cytoskeleton remodeling or WNT signaling [31]

3. Anti-cancer Effect

The anti-cancer potential of vitamin K has been the subject of research for several decades; its findings indicate that vitamin K (especially K2 and K3) can inhibit various types of cancer cells (ovarian cancer, leukemia, bladder cancer, hepatocellular carcinoma) through the induction of apoptosis or autophagy. The quinone moiety is present in the chemical structure of many cancer chemotherapeutic drugs such as anthracyclines daunorubicin, doxorubicin, mitoxantrone, or banoxantrone [34][35][36][37][38].
Various studies suggest different scenarios for the activity of vitamin K as an anticancer agent. In one study provided by Hitomi et al., treatment with vitamin K2 or K3 (400 µM) reduced the growth of hepatocellular carcinoma cells (HCC) implanted subcutaneously in mice [39]. An immunohistochemical evaluation of the tumors 53 days after inoculation revealed significant suppression of cyclin D1 and cyclin-dependent kinase 4 (CDK4) protein expression, and induced G1 cell cycle arrest and tumor growth inhibition. Subsequently, studies by Ozaki et al. confirmed that vitamin K2 inhibits the activity of the cyclin D1 promoter in an NFκB-dependent manner [40]. K2 has also been determined to inhibit IκB kinase (IKK) activity, thereby inhibiting the phosphorylation of IκBα (an inhibitor of NF-κB), thus preventing NF-κB activation and nuclear translocation (NF-κB is associated with cell growth and carcinogenesis) and cell cycle inhibition. Another study investigated the regulation of hepatoma-derived growth factor (HDGF) by K2 in hepatocellular carcinoma cells. It has been observed that vitamin K can also have an inhibitory effect on HCC cells by suppressing HDGF, as it significantly decreases protein expression [41]. Vitamin K2 can also induce cancer cell differentiation by modulating connexin gene expression [42]. Connexin (Cx) mediates intercellular communication that maintains tissue homeostasis, as the components of gap-junction connections ensure proper intercellular interactions, which are disturbed in neoplasms [43]. K2 can alter the expression pattern of connexins at the transcription level: it enhances the expression of Cx32 and suppresses Cx43, which inhibits proliferation and induces a normal liver phenotype.
K2 has been found to induce apoptosis in cancer cells. The use of K2 (30 µM) in the human promyelocytic cell line HL60 leads to changes in mitochondrial membrane potential, the release of cytochrome C, and induction of the apoptosis pathway mediated by the activation of Bak [Bcl-2 antagonist killer 1] [44]. Other data show that vitamin K may limit the survival of some pancreatic cancer lines (MiaPaCa2 and PL5). Its IC50 value was estimated to be 150 µM and 75 µM for K1 and K2, respectively. Inhibition of cell survival is mediated through apoptosis in the MAP kinase pathway. Vitamin K1 and K2 induce ERK phosphorylation in a time- and dose-dependent manner [45].
Vitamin K is also believed to exert anti-cancer activities by inducing autophagy. Depending on the level of cellular expression of Bcl-2, K2 may induce apoptosis or, in the case of Bcl-2 overexpression, direct the cell to autophagy [46]. In bladder cancer cells (T24), vitamin K2 significantly induces PI3K/Akt phosphorylation and increases expression of HIF-1α, intensifying glucose consumption and lactate formation. In response to the metabolic stress that arises, K2 triggers AMPK-dependent autophagic cell death [47]. Interestingly, a synthetic form of vitamin K, chloro-derivative menadione (VKT-2), also shows similar activity, inducing apoptosis and autophagy, and inhibits cell migration in liver tumor cells (HUH-7) [48]. In addition, the molecular goal of the analogue used was histone deacetylase (HDACS6) epigenetic regulatory protein. HDAC6 deacetylates not only histones but also cytoplasmic proteins such as α-tubulin, HSP90, p53, and cortactin. Using thermophoresis in microscales and enzymatic tests, VKT-2 was found to bind to HDAC6 and inhibit its activity resulting in hyperacetylation of α-tubulin, stabilization of microtubules and suppression of cell mobility. This suggests that vitamin K could be used in an epigenetic anti-cancer therapeutic strategy.
Another molecular target for vitamin K appears to be γ DNA polymerase. γ DNA polymerase maintains the mtDNA genome and its replication, and is responsible for all aspects of mitochondrial DNA from synthesis to repair. Mutsubara et al. showed the inhibitory effect of menadione on γ DNA polymerase by DNA polymerase tests [49]. Menadione selectively and dose-dependently inhibited the enzyme activity, reaching 50% inhibition at 6 µM menadione without affecting other polymerases. Interestingly, quinones with long side chains did not show the same activity as menadione. The authors postulate that the inhibitory effect of K3 is achieved through interaction with DNA as a template-DNA primer and inhibition of enzyme activity through direct interaction with γ DNA polymerase. This activity is related to the anti-angiogenic effect of menadione examined in an ex vivo and in vivo angiogenesis assay and indicates the function of K3 as an anti-tumor agent.
An interesting aspect of the K vitamins is their synergistic action with other compounds demonstrating anti-cancer activity. This is important in the context of combination therapy, which is a frequently used strategy in cancer treatment [50]. The combination of two or more drugs may lead to increased efficacy, multidirectional cellular activity, or the suppression of drug resistance, thus permitting lower doses. Greater benefits can be achieved if one of the combined agents is a micronutrient beneficial to health. Numerous studies indicate that the K vitamins have an additive or synergistic effect on various chemotherapeutic agents. Menadione has been found to be effective against multi-drug resistance in cancer cells by an additive effect with Mercaptopurine, Cytarabine, Hydroxyurea, VP-16, Vincristine, Doxorubicin, Mitoxantrone, or Mitomycin C, and synergistic effects with Fluorouracil, Cis-platin, and Dacarbazine. It only demonstrates an antagonistic effect when paired with methotrexate [51].
A strong synergism between K1 and sorafenib has been demonstrated in numerous studies [52][53][54][55]. Sorafenib (SFB), intended for the treatment of advanced kidney cancer and hepatocellular carcinoma, is an inhibitor of many kinases, both serine-threonine (RAF) and receptor tyrosine kinases (eg. ERK). It was observed that in HCC cells, K1 strongly enhances the sorafenib-induced inhibition of tumor cell proliferation [56]. Combined K1/SFB treatment allowed up to a 6.7-fold reduction in the concentration of sorafenib, with tumor reduction accompanied by reduced phosphorylation and inhibition of the RAF/MAPKK/ERK pathway. A similar observation was noted for pancreatic cancer cells when K1/SFB (50 µM/2.5 µM) was used, with a significant reduction in ERK and MEK phosphorylation, induction of apoptosis, and thus tumor regression [57].
K2 also has a chemosensitizing effect on cancer cells, with increased therapeutic benefits associated with SFB, 5-FU, or retinoid treatment [58][59][60]. The use of retinoids (analogs of vitamin A) and K2 resulted in synergistic inhibition of the Ras/ERK pathway in HCC and leukemia cells, triggered dephosphorylation of retinoid X receptors (RXR) and enabled their stimulation with retinoids [61], thus increasing apoptosis. Importantly, the K2/retinoid combination does not impair the growth and survival of normal hepatocytes. Interestingly, another micronutrient, tocopherol, can antagonize the anti-apoptotic effect of K2. As a strong antioxidant, tocopherol counteracted K2-mediated peroxide production and inhibited mitochondrial membrane polarization, which limited apoptosis in ovarian cancer cells [24].
In contrast to tocopherol, another micronutrient, ascorbic acid (AA), has a synergistic effect on K3 [13][62][63]. The AA/K3 association leads to an excessive increase in oxidative stress and a decrease in the potential of the mitochondrial membrane, which is a crucial trigger of tumor cell death [62][64][65]. This pairing enhances the effect of numerous chemotherapeutic agents. When tested with 13 chemotherapeutic agents (ABT-737, barasertib, bleomycin, BEZ-235, bortezomib, cisplatin, everolimus, lomustine, lonafarnib, MG-132, MLN-2238, palbociclib, and PI-103) AA/K3 demonstrated highly specific synergistic suppression of cancer cell growth at pharmacological concentrations; it produces metabolic changes that promote increased sensitivity of cancer cells to conventional anti-cancer therapy, while not adversely affecting normal cell survival [66].
According to the results of in vitro studies on cells, the data from a prospective EPIC-Heidelberg (European Prospective Investigation into Cancer and Nutrition–Heidelberg) cohort study, although not statistically significant, indicate that K2 treatment may have a positive effect on the therapy of cancer patients, reduce the risk of developing cancer, and lower mortality [67]. In a prospective study of 101,695 American adults, those with higher intakes of phylloquinone but not menaquinones had a lower risk of pancreatic cancer [68]. It has been suggested that increasing consumption of phylloquinone-rich foods may be an effective strategy for preventing pancreatic cancer. A study of the effect of the K2 analog menatetrenone on the recurrence rate of hepatocellular carcinoma (HCC) suggests that it may improve survival among patients treated surgically. Sixty patients were divided into two groups, one given a placebo and the other treated with 45 mg menatetrenone; it was found that menatetrenone significantly reduced the cumulative HCC recurrence rate (p = 0.0002) [69]. A meta-analysis of randomized control trials (RCT) and cohort studies on the effectiveness of K2 therapy in HCC patients showed that K2 can reduce the frequency of relapses and improve overall survival in HCC patients as early as one year after surgery [70].
 

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