June 2018
Fan Xv, Jiepeng Chen, Lili Duan, and Shuzhuang Li
Abstract
Despite the availability of multiple therapeutic methods for patients with cancer, the long-term prognosis is not satisfactory in a number of different cancer types. Vitamin K2 (VK2), which exerts anticancer effects on a number of cancer cell lines, is considered to be a prospective novel agent for the treatment of cancer.
The present review aims to summarize the results of studies in which VK2 was administered either to patients with cancer or animals inoculated with cancerous cells, particularly investigating the inhibitory effects of VK2 on cancerous cells, primarily involving cell-cycle arrest, cell differentiation, apoptosis, autophagy and invasion.
The present review summarizes evidence stating that treatment with VK2 could positively inhibit the growth of cancer cells, making it a potentially useful approach for the prevention and clinical treatment of cancer.
Additionally, the combination treatment of VK2 and established chemotherapeutics may achieve better results, with fewer side effects. Therefore, more attention should be paid to the effects of micronutrients on tumors.
Keywords: vitamin K2, cancer, drug therapy, cell-cycle arrest, cell differentiation, apoptosis
Introduction
Worldwide, cancer is the second-leading cause of mortality following cardiovascular disease. A certain proportion of several cancer types, including colorectal cancer, can only be diagnosed at an advanced stage (1). However, certain cancer types, such as hepatocellular carcinoma (HCC), can easily recur following a short duration despite effective treatment (2). In addition, certain other cancer types are accompanied by severe complications, including failure of the vital organs, despite diagnosis at an early stage and surgery is the contraindication. Established chemotherapies are not suitable for certain patients (1). Hence, the development of a novel therapeutic approach to enhance the overall prognosis of patients with cancer is essential.
Vitamin K (VK) is an essential lipid-soluble vitamin that is comprised of three types, VK1, VK2, and VK3. VK can activate coagulation factors (factor II, VII, IX, and X), protein C and protein S by facilitating γ-glutamyl carboxylase to catalyze the carboxylation of glutamic acid residues (3). In addition, VK-dependent γ-carboxylation has an essential role in maintaining bone homeostasis (4). A lack of VK can lead to severe neonatal bleeding and osteoporosis, which can be treated by the clinical application of VK2 (5).
Previous reports have demonstrated that VK1, VK2 and VK3 can inhibit several neoplastic cell lines at different levels, primarily by inducing apoptosis and cell cycle arrest of cancer cells (6), including HCC, leukemia, colorectal cancer, ovarian cancer, pancreatic cancer and lung cancer. Although the inhibition caused by VK3 is highly potent, VK3 is also highly toxic. By contrast, VK2 is milder, but causes no side effects, whereas VK1 has the least strong function (7). Hence, VK2 is a potential chemotherapeutic candidate for the treatment of cancer. The present review summarizes the results of VK2 against cancer in clinical, animal and in vitro experiments and aims to elucidate the mechanisms of anticancer effects of VK2.
Administration of VK2 in patients with cancer
To date, several case reports have highlighted the utility of VK2 as a potential antitumor agent. A prior study reported that daily administration of VK2 alleviated pancytopenia in an 80-year-old woman with myelodysplastic syndrome (MDS) and rendered red-cell transfusions redundant after 14 months (8). Similarly, a 72-year-old woman with relapsing acute promyelocytic leukemia was reported to attain complete remission following the combination treatment of VK2 and all-trans retinoic acid (9). Treatment with a combination of VK2 and an angiotensin-converting enzyme inhibitor was shown to shrink a hepatic dysplastic nodule in a 66-year-old Japanese woman with liver cirrhosis (10). Furthermore, the combination of VK2 and vitamin E suppressed the growth of the primary tumor and obliterated the intraperitoneal dissemination in a 65-year-old man with ruptured HCC (11).
These encouraging case reports led to several clinical studies on the anticancer functions of VK2. A multicenter pilot study on VK2 treatment of MDS and post-MDS acute myeloid leukemia (AML) revealed that VK2 could significantly reduce blastic cell numbers in the bone marrow and/or peripheral blood and enhance hematopoiesis, particularly in patients with post-MDS AML (12). Sada et al (13) demonstrated an association between improvements in hematopoiesis and the anti-apoptotic effect of VK2 on normal erythroid progenitors. In addition, the results of several studies (14–18) indicate that VK2 could potentially suppress the development and recurrence of HCC in patients. A study aiming to investigate the VK2-mediated prevention of osteoporosis in female cirrhotic patients deduced that VK2 may decrease the risk of HCC in female cirrhotic patients (14). Another study investigating the function of VK2 in patients with type C cirrhosis concluded that VK2 exerted inhibitory effects on HCC development in patients with type C cirrhosis (15). Mizuta et al (16) reported that VK2 could reduce the recurrence rates of HCC and enhance the survival rates. Kakizaki et al (17) investigated the effects of VK2 on recurrence in patients with HCC derived from HCV infection, with the results corroborating those obtained by Mizuta et al (16) Ishizuka et al (18) suggested that VK2 moderately inhibited HCC recurrence following curative hepatectomy. Although the results of certain studies (16–18) did not find statistically significant results, the majority of studies at present, except that conducted by Yoshida et al, considered VK2 as a valuable agent for clinical therapy in patients with cancer. Yoshida et al demonstrated that the VK2-dependent inhibition of HCC recurrence was not proven in a double-blind, randomized, placebo-controlled study (2). However, this study may have had problems with its design. First, Yoshida et al (2) enrolled patients with an increased recurrence and who had recurred after the first treatment. Second, the quality of VK2, which is susceptible to decrease following exposure to light, may also have affected the results. In addition, Zhong et al (19) conducted a meta-analysis based on six recent randomized control trials and one cohort study; the authenticity assessment of this meta-analysis was high. The results indicated that VK2 treatment could significantly decrease the 2- and 3-year tumor recurrence rate, but could not significantly decrease the 1-year recurrence rate, and could also increase the 1-, 2-, and 3-year survival rate (19). Overall, we hypothesize that VK2 can exert positive effects on the therapy of patients with cancer.
Anticancer effect of VK2 in animal research
Consistent with the results of clinical studies, data from animal studies indicated that VK2 treatment significantly inhibited tumor growth, without any evident side effects. For instance, exposing male BALB/c-nu/nu mice implanted with PLC/PRF/5 HCC cells to VK2 exhibited evident suppression of the growth of subcutaneous HCC tumors. In addition, decreases in cyclin D1 and cyclin-dependent kinase 4 (CDK4) levels indicated that VK2 may suppress tumor cells in vivo by inducing G1 arrest (7). Notably, mice bearing established colorectal cancer cells in the VK2 group exhibited no apparent changes compared with the control group, where the fur and weight of mice changed substantially. Following examination of apoptotic cells in vivo, researchers deduced that VK2 could potentially inhibit colorectal cancer cells by accelerating apoptosis (1). Hence, the induction of the cell-cycle arrest and apoptosis has a crucial role in the antitumor mechanism of VK2. Besides, it is established that VK2 could protect affected cells from forming precancerous lesions to reduce hepatocarcinogenesis in animals (20).
The combination of VK2 with other anticancer agents can be synergistic in tumor-bearing animals. For instance, pretreatment with VK2 prior to sorafenib treatment is proven to exert more effective HCC growth inhibition in animals than treatment with either alone (21). Similarly, VK2 and phosphatidylcholine together can exert a stronger inhibition on tumorigenesis, which can be applied to prevent hepatocarcinogenesis in patients at a high risk of HCC, particularly those with chronic hepatitis, while preserving the hepatic function (22). To summarize, animal studies have demonstrated that VK2 could repress cancer growth, which is likely to be associated with the induction of cell-cycle arrest and apoptosis.
Discussion
The present review summarizes the effects of VK2 on cancer in clinical, in vivo, and in vitro studies. Clinical trials demonstrated that VK2 has the potential to improve the prognosis of patients with cancer. In addition, evidence indicates that VK2 treatment can prevent HCC in patients with hepatic cirrhosis, and the dietary intake of VK2 can decrease the risk of developing cancer, particularly prostate and lung cancer (54). Furthermore, VK2 is confirmed to restrain tumor cell growth in animal studies (1,7,20–22,55), with cell-cycle arrest and apoptosis involved in this inhibition. In vitro studies (1,23–27,35) certified that VK2 could inhibit the growth of several cancer cell lines. Although several detailed links remain to be investigated, studies included in the present review (23–25,33–37,39,41,45,48,49) indicated that induction of the cell-cycle arrest, cell differentiation, apoptosis, and autophagy is crucial for VK2-dependent suppression of cancer cell growth. Certain protein kinases, such as PKA and PKC, signaling pathways, such as the MAPK pathways, transcription factors, such as NF-κB and AP-2, and essential proteins, such as Bak and Cx43, are involved in the mechanism of VK2 activity against cancer cells (23,24,33,37,41). The combination treatment of VK2 with other chemotherapeutics, such as sorafenib, can exert a synergistic effect and reduce adverse drug reactions.
In conclusion, VK2 can positively inhibit cancer cells. VK2 appears to be an extremely promising agent with very limited toxicity, which can be a useful option for prevention of cancer and clinical therapy of cancer. However, the inhibition of vitamin K and D in cancers indicated that vitamins might have positive effects on the prevention and therapy of tumors. Therefore, the effects of vitamins or minerals on tumors should be investigated further.
