Vitamin K3 (menadione) inhibits the growth of mammalian tumor cells in culture

Prasad, Kedar N.; Edwards‐Prasad, Judith; Sakamoto, Arthur

doi:10.1016/0024-3205(81)90683-4

Cited by 72 publications

(48 citation statements)

References 7 publications

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“…VK 3 is a synthetic derivative of VK 1 that exhibits broadspectrum anticancer activity in vitro against human breast, cervix, nasopharynx, stomach, colon, liver, lung, leukemia, as well as lymphoma cell lines (Prasad et al, 1979a;Noto et al, 1989;Ngo et al, 1991;Nutter et al, 1991;Wu et al, 1993aWu et al, , 1993b. VK 3 has also been shown to be cytotoxic to a variety of urological tumors (Venugopal et al, 1996a(Venugopal et al, , 1996bErvin et al, 1998;Gilloteaux et al, 1998aGilloteaux et al, , 1998bGilloteaux et al, , 1999aGilloteaux et al, , 2001aGilloteaux et al, , 2001bGilloteaux et al, , 2001cGilloteaux et al, , 2005Jamison et al, 2004Jamison et al, , 2005.…”

Section: Menadione Cytotoxicitymentioning

confidence: 99%

Morphology and DNA degeneration during autoschizic cell death in bladder carcinoma T24 cells induced by ascorbate and menadione treatment

Gilloteaux¹,

Jamison²,

Arnold³

et al. 2005

Anat. Rec.

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Feulgen and actin-phalloidin staining as well as gel electrophoresis have been employed in conjunction with cell ultrastructure to describe the effects of 1-, 2-, and 4-hr ascorbate (VC), menadione (VK 3 ), and ascorbate:menadione (VC:VK 3 ) treatments on the T24 human bladder carcinoma cell line. T24 cells exposed to VC alone display blebs and other superficial membrane defects related to membrane alterations and to superficial cytoskeleton changes. VK 3 treatment damages the cell nucleus and organelles, leads to the redistribution of the organelles in the perikaryon as a consequence of cytoskeletal damage, and results in cytoplasmic self-excisions. After VC:VK 3 treatment, the cells show exaggerated alterations characteristic of each vitamin treatment alone, including damaged mitochondria, self-excision of organelle-free pieces of cytoplasm, and extrusion of the perikaryon containing a nucleus surrounded by the damaged organelles. The nuclear envelope appears intact and contains chromatin that decondenses and dissipates. During the cellular demise that concludes with apparent karyolysis, the cells significantly decrease their size and alter their shape. However, the cisterns of rough endoplasmic reticulum are undamaged, but may become dilated. Since the cellular phenomena leading to cell death differ morphologically from apoptosis and necrosis, but entail selfcutting without nuclear bodies, this new form of cell death was called autoschizis. In addition, gel electrophoresis and Feulgen staining demonstrate that autoschizis is accompanied by random DNA degeneration.

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Section: Menadione Cytotoxicitymentioning

confidence: 99%

Morphology and DNA degeneration during autoschizic cell death in bladder carcinoma T24 cells induced by ascorbate and menadione treatment

Gilloteaux¹,

Jamison²,

Arnold³

et al. 2005

Anat. Rec.

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“…Its anti-tumor and cytotoxic effects were thought to involve redox cycling (Begleiter, 1983;Rotilio et al, 1985). Compared with other quinone agents, such as doxorubicin and daunorubicin, vitamin K3 was shown to possess a broad spectrum of anti-tumor activity, including action against multidrug-resistant tumor cells (Prasad et al, 1981;Thor et al, 1982;Akman et al, 1985;Chlebowski et al, 1985;Nutter et al, 1991; Juan and Wu, 1993;Osada et al, 2001). There seem to be two possible mechanisms of growth inhibition by vitamin K3.…”

Section: Vitamin K As a Growth Inhibitormentioning

confidence: 99%

“…Comparing vitamins K1, K2, and K3, only the synthetic vitamin K3 shows strong growth inhibitory effects on many cell types in vitro and in vivo (Prasad et al, 1981;Chlebowski et al, 1985;Noto et al, 1989;Wu et al, 1993;Wang et al, 1995). The mechanisms of this growth inhibition have been ascribed to both oxidative stress due to its redox cycling activity (Wilson et al, 1987;Gant et al, 1988) as well as to arylation of cellular thiols at position 3 of the naphthoquinone nucleus (Thor et al, 1982;Ross et al, 1986;Brown et al, 1991;Nutter et al, 1992).…”

Section: Mechanisms Of Cell Growth Inhibition By K Vitamin Analogs Prmentioning

confidence: 99%

K vitamins, PTP antagonism, and cell growth arrest

Carr

Wang

Kar

2002

Journal Cellular Physiology

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The main function of K vitamins is to act as co-factors for g-glutamyl carboxylase. However, they have also recently been shown to inhibit cell growth. We have chemically synthesized a series of K vitamin analogs with various side chains at the 2 or 3 position of the core naphthoquinone structure. The analogs with short thio-ethanol side chains are found to be more potent growth inhibitors in vitro of various tumor cell lines. Cpd 5 or [2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone] is one of the most potent. The anti-proliferation activity of these compounds is antagonized by exogenous thiols but not by non-thiol antioxidants. This suggests that the growth inhibition is mediated by sulfhydryl arylation of cellular glutathione and cysteine-containing proteins and not by oxidative stress. The protein tyrosine phosphatases (PTP) are an important group of proteins that contain cysteine at their catalytic site. PTPs regulate mitogenic signal transduction and cell cycle progression. PTP inhibition by Cpd 5 results in prolonged tyrosine phosphorylation and activation of several kinases and transcription factors including EGFR, ERK1/2, and Elk1. Cpd 5 could activate ERK1/2 either by signaling from an activated EGFR, which is upstream in the signaling cascade, or by direct inhibition of ERK1/2 phosphatase(s). Prolonged ERK1/2 phosphorylation strongly correlates with Cpd 5-mediated growth inhibition. Cpd 5 can also bind to and inhibit the Cdc25 family of dual specific phosphatases. As a result, several Cdc25 substrates (Cdk1, Cdk2, Cdk4) involved in cell cycle progression are tyrosine phosphorylated and thereby inhibited by its action. Cpd 5 could also inhibit both normal liver regeneration and hepatoma growth in vivo. DNA synthesis during rat liver regeneration following partial hepatectomy, transplantable rat hepatoma cell growth, and glutathione-S-transferase-pi expressing hepatocytes after administration of the chemical carcinogen diethylnitrosamine, are all inhibited by Cpd 5 administration. The growth inhibitory effect during liver regeneration and transplantable tumor growth is also correlated with ERK1/2 phosphorylation induced by Cpd 5. Thus, Cpd 5-mediated inhibition of PTPs, such as Cdc25 leads to cell growth arrest due to altered activity of key cellular kinases involved in signal transduction and cell cycle progression. This prototype K vitamin analog represents a novel class of growth inhibitor based upon its action as a selective PTP antagonist. It is clearly associated with prolonged ERK1/2 phosphorylation, which is in contrast with the transient ERK1/2 phosphorylation induced by growth stimulatory mitogens.

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“…The synthetic vitamin K 3 (2-methyl-1,4-naphthoquinone or menadione) has been reported to inhibit growth of many cell types both in vitro and in vivo (1)(2)(3)(4)(5). The mechanisms of this growth inhibition have been ascribed to both oxidative stress due to its redox cycling activity (6 -8) and arylation of cellular thiols at position 3 of the naphthoquinone nucleus (9 -12).…”

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confidence: 99%

Inhibition of Hepatoma Cell Growth in Vitro by Arylating and Non-arylating K Vitamin Analogs

Nishikawa¹,

Wang²,

Kerns³

et al. 1999

Journal of Biological Chemistry

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We recently found that a thioether analog of K vitamin (Cpd 5) inhibited the activity of protein-tyrosine phosphatases (PTPases) and induced protein-tyrosine phosphorylation in a human hepatoma cell line (Hep3B). We have now examined the structural requirements for induction of protein-tyrosine phosphorylation and PTPase inhibition by several K vitamin analogs. Thioether analogs with sulfhydryl arylation capacity, especially those with a hydroxy (Cpd 5) or a methoxy group at the end of the side chain, induced protein-tyrosine phosphorylation, but non-arylating analogs, such as those with an all-carbon or O-ether side chain, did not. Among the receptor-tyrosine kinases, epidermal growth factor receptors were tyrosine-phosphorylated by treatment with thioether analogs, whereas insulin and hepatocyte growth factor receptors were not. An increase in tyrosine-phosphorylated ERK2 mitogen-activated protein kinase was also observed. The activity of purified T cell PTPase was inhibited only by the thioether analogs, but not by non-arylating analogs. Furthermore, the epidermal growth factor receptor dephosphorylation activity of Hep3B cell lysates was inhibited by Cpd 5 treatment. A similar induction of protein-tyrosine phosphorylation by Cpd 5 was seen in other human hepatoma cell lines together with growth inhibition. However, one cell line (HepG2), which was relatively resistant to growth inhibition by Cpd 5, did not increase its phosphorylation levels upon Cpd 5 treatment. These results suggest that cell growth inhibition by thioether analogs is closely associated with inhibition of PTPases by sulfhydryl arylation and with tyrosine phosphorylation of selected proteins.

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Vitamin K3 (menadione) inhibits the growth of mammalian tumor cells in culture

Cited by 72 publications

References 7 publications

Morphology and DNA degeneration during autoschizic cell death in bladder carcinoma T24 cells induced by ascorbate and menadione treatment

Morphology and DNA degeneration during autoschizic cell death in bladder carcinoma T24 cells induced by ascorbate and menadione treatment

K vitamins, PTP antagonism, and cell growth arrest

Inhibition of Hepatoma Cell Growth in Vitro by Arylating and Non-arylating K Vitamin Analogs

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