ALTERNATIVE CANCER SOLUTION

 Alternative Cancer Treatment - Articles

Vitamin K2
Vitamin K is one of the fat-soluble vitamins, yet it has received far less attention from the supplement-consuming public than its more famous “cousins” A, D and E. Discovered in 1929 in Denmark, vitamin K was thought to be useful only to promote normal blood coagulation, as part of the complex “clotting cascade” that keeps us from bleeding to death from cuts or broken internal blood vessels. Vitamin K even got its name from the first letter of the Danish word koagulation.

Research over the last 25 years has gradually given a new and more expanded view of the role of K. It is now known to be essential for bone health, and may also be important to prevent atherosclerosis and calcified arterial plaque. It may also be crucial for brain health.

The Three Forms of K
The term “vitamin K” refers to a family of related compounds, whose members all have the basic “clotting power” of K (Fig. 1). Vitamin K1 (phylloquinone or phytonadione) is formed by plants, and is the main dietary source of K. A diet high in green vegetables such as kale, spinach, broccoli, lettuce and cabbage might provide hundreds of micrograms of K1 per day.1 The FDA’s RDA (recommended daily allowance) for K is 80 mcg per day. Vitamin K2 (menaquinones, menatetrenone) refers to a group of related compounds, menaquinones 2-9. Some menaquiones are produced by our gut bacteria, but the evidence suggests this K2 is poorly absorbed, if at all.2,3 Humans and animals normally convert some ingested K1 to menaquinone-4 (MK4), also called menatetrenone.4,5 This is the specific mammalian K2. Vitamin K3 (menadione) has the same naphthoquinone “head” as K1 and K2, but lacks a side chain. K3 is a synthetic form of K.1.

K and Bone Health
Studies conducted with humans and animals over the past 20 years have gradually made it clear that vitamin K is essential to optimal bone health, especially among post-menopausal women and elderly men. Yet it is the K2 form that has been shown to be the bone builder. Kaneki and colleagues in Japan compared K2 levels in the blood of 24 women with osteoporotic vertebral fractures and 36 elderly women without fractures. Serum levels of K1 were virtually identical in both groups, yet serum levels of MK7 (a K2 form found in soy natto, a popular Japanese food) were twice as high in the nonfracture group compared to the fracture group.6.

Japanese women tend to suffer much less osteoporosis fractures than Western women. A recent study found that fracture incidence within Japan was strongly correlated to natto intake and blood serum levels of MK7. MK7 levels were 5.26 ng/mL in Tokyo women, 1.22 in Hiroshima, and 0.37 in British women. Natto consumption is high in Tokyo, lower in Hiroshima, and non-existent in Britain. The authors concluded: “A statistically significant inverse correlation was found between incidence of hip fractures in women and natto consumption [chief dietary source of MK7] in each prefecture [district] throughout Japan.”7 In other words, the more natto, the more MK7, and the fewer fractures.

Menatetrenone (K2) and Bone Health
The Japanese have pioneered the use of K2 (menatetrenone, or MK4) supplements to treat osteoporosis. Rat studies showed the safety and efficacy of K2.8,9,10 Over the past decade, more than a dozen human clinical trials have shown the safety and efficacy of K2 to treat a variety of forms of osteoporosis. The protocol for K2 use is consistent throughout these studies: 15 mg K2 taken three times per day with fat-containing meals. Adequate dietary fat is essential for optimal K2 absorption.11.

Many of the studies have focused on K2’s ability to reverse, or at least seriously slow down, post-menopausal osteoporosis. Due to the decrease in bone-friendly estrogen after menopause, osteoporosis with consequent fractures is common among women.

One 24-month study compared K2 to the biphosphonate drug etidronate, with the control group getting only a calcium supplement. After two years, both the etidronate and K2 groups had significant increases in bone mineral density compared to the control group, with etidronate doing even better than the K2. Yet the incidence of new vertebral fractures was radically less in both the K2 and etidronate groups: 65 percent and 70 percent less than the control groups, respectively.12.

Another study found that “a combination of risedronate and vitamin K2 has a synergistic effect on preventing the deterioration of trabecular bone architecture induced by estrogen deficiency. Some studies have shown that combined treatment with etidronate and vitamin K2 appears to be more effective than etidronate alone in the prevention of new osteoporotic vertebral fractures.”13 Other studies have found that the combination of vitamin D3 and K2 works better than D3 or K2 alone in increasing bone mineral density in postmenopausal osteoporotic women.14 Yet other studies have obtained excellent results in increasing bone mineral density/reducing fracture rates with just 45 mg K2 per day.15,16.

Menatetrenone (K2) and Bone Health
The Japanese have pioneered the use of K2 (menatetrenone, or MK4) supplements to treat osteoporosis. Rat studies showed the safety and efficacy of K2.8,9,10 Over the past decade, more than a dozen human clinical trials have shown the safety and efficacy of K2 to treat a variety of forms of osteoporosis. The protocol for K2 use is consistent throughout these studies: 15 mg K2 taken three times per day with fat-containing meals. Adequate dietary fat is essential for optimal K2 absorption.11.

K2 has been used clinically to treat other forms of osteoporosis with success as well. K2 has successfully prevented the bone loss that normally occurs in kidney dialysis patients.17,18 K2 stopped bone loss in liver cirrhosis patients.19 In an 11-month study of recovering anorexia patients, K2 cut bone loss 60 percent compared to the control group.20 In a 12-month study of 120 female Parkinson’s disease patients, the fracture incidence in the K2 group was only 10 percent of the control group’s fracture rate!21 K2 also increased bone mineral density and reduced the fracture rate in a 12-month study of 108 stroke patients with one-sided paralysis.22.

K2: Multiple Effects
K2 has been shown to help build strong bones through multiple mechanisms. It protects osteoblasts, the cells that build new bone, from apoptosis (programmed cell death).23 K2 also causes many mature osteoclasts to undergo apoptosis, and inhibits the formation of new ones.24 Osteoclasts are the cells that destroy existing bone. While some are necessary, with aging and osteoporosis osteoclasts become more numerous, while osteoblasts become fewer in number. So bone destruction overwhelms bone building. K2 also inhibits the formation and bone-destroying activity of prostaglandin E2 (PGE2), an inflammatory eicosanoid intimately involved at the molecular level in promoting bone breakdown.25,26 Another study that showed K2 inhibited the bone-destroying activity of PGE2 also found that K1 had no PGE2-inhibiting activity.27 K2 also preserves the microstructure of trabecular bone, the spongy bone found at the ends of long bones, which tends to disintegrate with age or osteoporosis.28,29 K2 also opposes the bone-destroying effects of glucocorticoids (cortisol, prednisone).30,31.

K2 and Cancer
In 1994 it was reported that K2, but not K1, could promote the differentiation of various types of leukemia cells. “Leukemia” is a broad, general term used to describe various malignant blood cell diseases which involve abnormally large numbers of immature white cells and damaged bone marrow. If not successfully treated, leukemia is usually eventually fatal. Toxic chemotherapy drugs are often used to treat it. By causing the leukemia cells to differentiate, K2 helps the cells to transform into more normal, nonleukemic cells. According to the study, “[Vitamin] K2 may be safely used in differentiation therapy [of leukemia] in combination with other inducers.”32 In 1997, another research group reported that K2 “showed a potent apoptosis-inducing activity for all freshly isolated leukemia cells tested” but that K1 had no anti-leukemia activity.33.

By 2001, a Japanese research group had found that K2 had a dual effect, depending on the unique genetic makeup of the various leukemia cells tested. K2 killed some leukemia cells by apoptosis, and those that were genetically resistant to K2’s apoptotic activity were stimulated to differentiate instead. Miyazawa and colleagues concluded: “The dichotomous nature of [vitamin] K2 against leukemia cells appears to have clinical benefits for the treatment of patients with leukemias and myelodysplastic syndromes.”34

In 2003, the Miyazawa group published a study showing that K2 could kill (by apoptosis) a variety of different types of lung cancer cells, including small cell carcinomas, adenocarcinomas, squamous cell carcinomas and large-cell carcinomas. “Since [vitamin] K2 is a safe medicine without prominent adverse effects…our data strongly suggest the therapeutic possibility of using [vitamin] K2 for the treatment of patients with lung carcinoma.”35

In 2004 another Japanese research group found that K2 inhibits the growth and invasion of hepatocellular carcinoma (liver cancer) cells both in vitro and in vivo. Giving K2 to “mice inoculated with liver tumor cells reduced both tumor growth and body weight loss.”36 In July, 2004, the first human clinical trial results were announced in JAMA (The Journal of the American Medical Association). Forty women diagnosed with viral liver cirrhosis between 1996 and 1998 were randomly assigned either to a group receiving 45 mg K2 daily or the control group. By the end of the study, two of 21 women given K2 had developed liver cancer, while nine of 19 control group women had developed liver cancer. The results were found to be statistically significant, and a role for K2 in preventing liver cancer was proven.37

K2: Your Arteries’ Best Friend?
Animal studies have shown that K2, but not K1, can inhibit the calcification of arterial plaque. As a recent review notes: “Calcification of the vessel walls is one of the features of atherosclerosis and is by itself considered to be a risk factor for plaque rupture.”38 And plaque rupture in a heart artery is often the final trigger for a (possibly fatal) myocardial infarction (heart attack). A 1996 study found that high-dose K2 inhibited the increase in aortic or kidney calcium induced by megadose synthetic vitamin D2. The authors noted that “a pharmacological dose of vitamin K2 might have a usefulness for the prevention and treatment of arteriosclerosis with calcification.”39 A 1999 study found that high-dose K2 could inhibit the increase in aortic calcium in rats made arteriosclerotic by high-dose D2 and an atherogenic diet.40

A 1997 rabbit study found that high dose K2 “prevents both the progression of atherosclerosis and the coagulative tendency by reducing the total-cholesterol, lipid peroxidation and factor X activity in plasma, and the ester cholesterol deposition in the aorta of hypercholersterolemic rabbits.”41 In 2003 Spronk and colleagues reported “that MK-4 [K2] and not K1 inhibits warfarin-induced arterial calcification.”42

Most importantly, a study published in 2001 examined more than 4,000 humans followed from 1990 to 1996. Subjects were examined for their dietary K2 intake. Those with a “high” K2 intake (greater than 33 mcg per day) had only 43 percent of the risk of suffering a heart attack compared to the low K2 group (less than 22 mcg per day). The risk of dying from a heart attack was only 37 percent as high in the high-K2 group compared to the low-K2 group. “The dietary intake of vitamin K1 showed no consistent relation with cardiac events or aortic atherosclerosis.”43

K2: Anti-Aromatase?
One intriguing study on male rats suggests that K2 might be useful in suppressing the excess estrogen all too common in aging men. When aging male rats were fed a calcium-deficient diet, their serum estradiol levels rose 430 percent. K2 significantly reduced the elevated estrogen levels. The estrone level in serum of the K2-fed rats fell to a level lower than the control rats fed a regular calcium diet. The study’s authors suggest that K2 suppressed testicular aromatase in calcium deficient rats, reducing estrogen production, and that the increased estrogen production in the calcium-deficient rats not given K2 might be a compensating mechanism to prevent osteoporosis.44 This in turn suggests that the frequent elevation of estrogen seen in aging men might be the body’s way of preventing osteoporosis, which is more common in women than men. Taking high-dose K2 just might suppress male aromatase activity, suppressing male estrogen overproduction, yet still prevent osteoporosis.

Megadose K2: Safety
The high dose of 45 mg K2 daily has been used in dozens of human studies, many lasting one to two years. Many of these studies emphasize the safety of K2. “Administration of menatetrenone [MK4/K2] was well tolerated. Given the absence of toxicity, menatetrenone can be recommended for all patients with MDS-RA.”45 “The adverse events were 2 cases of mild skin rash [out of 43 patients] which subsided after cessation of medication.”16 “menatetrenone can be used safely for [at least] 1 year in CAPD patients.”17 “No adverse effects of vitamin K2 were noted.”19 “No adverse effect was observed.”30

One concern some people might have with high-dose K2 is that it might cause “overcoagulation” of the blood. The 1997 rabbit study previously mentioned specifically noted that “The excessive dose of vitamin K2…did not promote the coagulative tendency in the rabbits.”41

A 2001 study very carefully examined a range of variables that might indicate excessive blood-clotting tendency due to high-dose K2 in 29 elderly patients. The authors noted: “No changes in the sensitive molecular markers such as TAT and F1+2, which reflect the amount of thrombin [a pro-clotting substance] generated in the bloodstream, were observed…These results indicate that MK4 [K2] can be administered safely, with regard to maintaining the hemostatic balance [normal blood clotting], to osteoporotic patients receiving no anticoagulant therapy.”46

The one caution in using high-dose K2 is the use of warfarin (Coumadin®) anticoagulant therapy. Anyone taking warfarin or other similar “blood-thinning” drugs must NOT use high-dose K2. Indeed, such patients are usually counseled to avoid even high K1-containing foods, such as green vegetables, since warfarin works by opposing vitamin K’s blood coagulation effects.

Menatetrenone, a Vitamin K2 Analogue, Inhibits Hepatocellular Carcinoma Cell Growth by Suppressing Cyclin D1 Expression through Inhibition of Nuclear Factor B Activation
Iwata Ozaki1,2, Hao Zhang1,3, Toshihiko Mizuta1, Yasushi Ide1, Yuichiro Eguchi1, Tsutomu Yasutake1, Toshiyuki Sakamaki4, Richard G. Pestell4 and Kyosuke Yamamoto1

Authors' Affiliations: 1 Division of Hepatology and Metabolism, Department of Internal Medicine, and 2 Health Administration Center, Saga Medical School, Saga University, Nabeshima, Saga, Japan; 3 Second Department of Surgery, China Medical University, Heping District, Shenyang, China; and 4 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia

Requests for reprints: Iwata Ozaki, Health Administration Center, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. Phone: 81-952-34-3215; Fax: 81-952-34-2017;

Purpose:
Menatetrenone, a vitamin K2 analogue, plays an important role in the production of blood coagulation factors. Menatetrenone has also bee shown to have antineoplastic effects against several cancer cell lines including hepatocellular carcinoma (HCC) cells. However, the mechanisms by which vitamin K2 inhibits HCC cell growth have not bee fully clarified, and we therefore investigated the molecular basis of vitamin K2–induced growth inhibition of HCC cells.

Experimental Design:
HCC cells were treated with vitamin K2 and the expression of several growth-related genes including cyclin-dependent kinase inhibitors and cyclin D1 was examined at the mRNA and protein levels. A reporter gene assay of the cyclin D1 promoter was done under vitamin K2 treatment. The regulation of nuclear factor B (NF- B) activation was investigated by a NF- B reporter gene assay, an electrophoretic mobility shift assay, a Western blot for phosphorylated I B, and an in vitro kinase assay for I B kinase (IKK). We also examined the effect of vitamin K2 on the growth of HCC cells transfected with p65 or cyclin D1.

Results:
Vitamin K2 inhibited cyclin D1 mRNA and protein expression in a dose-dependent manner in the HCC cells. Vitamin K2 also suppressed the NF- B binding site-dependent cyclin D1 promoter activity and suppressed the basal, 12-O-tetradecanoylphorbol-13-acetate (TPA)–, TNF- –, and interleukin (IL)-1–induced activation of NF- B binding and transactivation. Concomitant with the suppression of NF- B activation, vitamin K2 also inhibited the phosphorylation and degradation of I B and suppressed IKK kinase activity. Moreover, HCC cells overexpressing cyclin D1 and p65 became resistant to vitamin K2 treatment.

Conclusion:
Vitamin K2 inhibits the growth of HCC cells via suppression of cyclin D1 expression through the IKK/I B/NF- B pathway and might therefore be useful for treatment of HCC.

Vitamin K2 may curb liver cancer in women with viral cirrhosis
Reuters Health
Last Modified: November 1, 2001
Last Updated: 2004-07-21 10:42:10 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Daily vitamin K2 supplementation may help prevent the development of hepatocellular carcinoma in women with viral cirrhosis of the liver, Japanese researchers report in the July 21st issue of the Journal of the American Medical Association.

Dr. Susumu Shiomi and colleagues from Osaka City University previously reported that daily vitamin K2 prevented bone loss in women with cirrhosis of the liver. (See Reuters Health report May 27, 2002). "The women in this original trial also satisfied criteria required for examination of the effects of vitamin K2 on the development of liver cancer," Dr. Shiomi told Reuters Health.

In all, 40 women with viral liver cirrhosis who were admitted to the hospital between 1996 and 1998 were randomly assigned to 45 milligrams per day of vitamin K2 or to no vitamin K2. All women received dietary advice and symptomatic therapy for ascites as needed.

Liver cancer was detected in 2 of the 21 patients given vitamin K2 and 9 of the 19 controls. Thus, Dr. Shiomi reported that "the cumulative proportion of patients with liver cancer was smaller in the treated group."

After adjusting for factors including age, alanine aminotransferase activity, serum albumin, and total bilirubin, the risk ratio for the development of liver cancer in vitamin K2-treated women was 0.13.

"Despite its small size," the authors note, "our study indicates that vitamin K2 decreases the risk of hepatocellular carcinoma to about 20% compared with the control group, suggesting that vitamin K2 may delay the onset of hepatocarcinogenesis."

JAMA 2004;292:358-361.

Vitamin K2-induced antitumor effects via cell-cycle arrest and apoptosis in gastric cancer cell lines.
Third Department of Surgery and First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.Vitamin K2 (VK2) has a growth inhibitory effect on various types of cancer cells in vitro, and its efficacy has been demonstrated in clinical applications in a number of patients with leukemia and hepatocellular carcinoma. In this study, the effect of cell growth inhibition and apoptosis induction and the concomitant use of an anticancer agent by VK2 (menaquinone: MK4), on gastric cancer cell lines were examined. When 4 kinds of gastric cancer cells (KATO III, MKN7, MKN74 and FU97) were exposed to MK4, the cell growth was inhibited in an MK4 dose-dependent manner. Morphologically, apoptosis induced by MK4 was recognized in FU97, but only a slight number of apoptotic images was recognized in other cell lines. On the contrary, in all the cell lines, the percentage of APO2.7 positive cells increased significantly in the MK4-treated group as compared to the controls. Caspase-3 activity increased significantly in KATO III and FU97 as compared to the controls, while no significant differences were noted in MKN7 or MKN74. Moreover, in all the cell lines, the percentage of G0/G1-phase cells ( approximately 70% in KATO III and FU97, and > or =80% in MKN7 and MKN74) increased in comparison to the controls, suggesting that cell-cycle arrest had occurred. All of the gastric cancer cell lines were given MK4 in different concentrations and two kinds of anticancer agent, with the result that cell growth was inhibited by the anticancer agent in a dose-dependent manner when it was given with MK4 in concentrations of up to 10 microM. In conclusion, our results demonstrate that the effect of MK4 on apoptosis and cell-cycle arrest differs in differentiated (MKN7, MKN74) and undifferentiated (KATO III, FU97) gastric cancer cell lines, and that MK4 alone or with anticancer agents has an antitumor effect on gastric cancer cell lines.

Int J Oncol.  2005; 26(1):33-40 
Yokoyama T; Miyazawa K; Yoshida T; Ohyashiki K
First Department of Internal Medicine, Tokyo Medical University, Nishishinjuku, Shinjuku-ku, Tokyo, Japan

Imatinib mesylate, an inhibitor of tyrosine kinases including BCR-ABL and KIT, inhibits the growth inhibition of small cell lung cancer (SCLC) cell lines in vitro. However, clinical trials of imatinib mesylate alone in patients with SCLC resulted in unsatisfactory outcomes. Vitamin K2 (menaquinone-4: VK2) induces apoptosis and differentiation in leukemia cells. We recently reported that VK2 also induces apoptosis in lung cancer cell lines. In the present study, we focused on the in vitro combined effects of imatinib mesylate plus VK2 on SCLC cell lines such as LU-139, LU-130, NCI-H69 and NCI-H128. Treatment with imatinib mesylate and VK2 for 96 h resulted in suppression of cell growth in a dose-dependent manner in all cell lines tested. The 50% inhibitory concentration (IC50) for imatinib mesylate ranged from 17-29 microM, whereas the IC50 for VK2 ranged from 16-64 microM. Combined treatment of imatinib mesylate plus VK2 resulted in pronounced inhibition of cell growth. The morphologic features of cells treated with imatinib mesylate and VK2 were typical of apoptosis. Since VK2 is a safe medicine without prominent adverse effects, treatment of patients with SCLC could derive therapeutic benefits from a combination of imatinib mesylate and VK2.