Vitamin K2, a Naturally Occurring Menaquinone, Exerts Therapeutic Effects on Both Hormone-Dependent and Hormone-Independent Prostate Cancer Cells
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767046/Abstract
In recent years, several studies have shown that vitamin k2 (VK2) has anticancer activity in a variety of cancer cells. The antitumor effects of VK2 in prostate cancer are currently not known. In the present study, we sought to characterize the anticancer potential of VK2 in both androgen-dependent and -independent prostate cancer cells. Our investigations show that VK2 is able to suppress viability of androgen-dependent and androgen-independent prostate cancer cells via caspase-3 and -8 dependent apoptosis. We also show that VK2 treatment reduces androgen receptor expression and PSA secretion in androgen-dependent prostate cancer cells. Our results also implicate VK2 as a potential anti-inflammatory agent, as several inflammatory genes are downregulated in prostate cancer cells following treatment with VK2. Additionally, AKT and NF-kB levels in prostate cancer cells are reduced significantly when treated with VK2. These findings correlated with the results of the Boyden chamber and angiogenesis assay, as VK2 treatment reduced cell migration and angiogenesis potential of prostate cancer cells. Finally, in a nude mice model, VK2 administration resulted in significant inhibition of both androgen-dependent and androgen-independent tumor growth. Overall, our results suggest that VK2 may be a potential therapeutic agent in the treatment of prostate cancer.
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1. Introduction
Prostate cancer is the most common solid malignancy in men. In the USA, it is estimated that 241,740 new cases and 28,170 deaths will occur in 2012 [1]. Prostate cancer is currently treated with a combination of surgery, androgen ablation or radiation therapy. Those undergoing hormonal therapy eventually develop aggressive hormone unresponsive disease. Hence, one of the major focuses in prostate cancer research is the discovery of better chemotherapeutic agents for the advanced hormone-resistant, metastatic form of this disease.
Vitamin k is a fat soluble vitamin that plays a major role in the clotting cascade by acting as a coenzyme for a vitamin k dependent carboxylase that catalyzes the carboxylation of glutamic acid residues to produce gamma-carboxyglutamic acid [2]. Vitamin k also appears to work in regulation of bone metabolism through a similar mechanism via gamma carboxylation of bone matrix proteins [3]. There are two naturally-occuring vitamin k compounds, vitamin k1 (phylloquinone) and vitamin k2 (menaquinone). Interestingly, vitamin k2 (VK2) intake seems to be associated with greater benefits of reduced coronary calcification when compared to vitamin k1 consumption [4]. In recent years, various reports have shown that VK2 has antioncogenic effects in various cancer cell lines, including leukemia, lung cancer, ovarian cancer, and hepatocellular cancer [5–9]. Although the exact mechanisms by which VK2 exert its antitumor effect are still unclear, processes such as cell cycle arrest, apoptosis and induction of differentiation appear to contribute to the therapeutic effects of VK2 [5–9]. The antitumor effects of VK2 have been most extensively studied in hepatocellular cancer. Yamamoto and colleagues showed that downregulation of hepatoma-derived growth factor is partially responsible for the growth suppression properties of VK2 in hepatocellular cell lines [10]. In another study, Otsuka and colleagues showed that VK2 inhibits growth and invasion of hepatocellular cell lines via activation of protein kinase A [11]. Recent studies also suggest a role for VK2 in the prevention of cancer, as a randomized trial of 43 women with viral hepatitis treated with high dose VK2 showed an 80% decreased risk of developing hepatocellular carcinoma [12].
In view of VK2 potential to reduce osteoporosis [13] and atherosclerosis risk [4] and given the fact that these two pathologies are frequently associated with prostate cancer patients undergoing hormonal therapy [14, 15], development of VK2 as a treatment strategy for prostate cancer would have far reaching impact on prostate cancer patients. Previously, Nimptsch et al. showed an inverse relationship between dietary intake of VK2 and risk of prostate cancer [16]. Interestingly, serum undercarboxylated osteocalcin (ucOC), a biomarker of vitamin k status, is inversely associated with VK2 intake and the development of advanced prostate cancer [17]. These studies thus suggest that the intake of VK2 may be beneficial in preventing the progression of prostate cancer. Moreover, VK2 is also shown to enhance the chemotherapeutic efficacy of conventional anticancer drug Sorafenib in hepatocellular carcinoma [18]. Unlike its synthetic counterpart, vitamin k3, there are no known side effects associated with ingestion of high doses of VK2 [19]. To date, however, no studies have been conducted to assess the therapeutic potential of VK2 in the treatment of prostate cancer. To our knowledge, this is the first comprehensive study which demonstrates the therapeutic potential of VK2 against both forms of prostate cancer (hormone dependent and hormone independent) using in vitro and in vivo models with mechanistic details of VK2 action.
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