Vitamin K and hepatocellular carcinoma: The basic and clinic

Abstract

Vitamin K (VK), which was originally identified as a cofactor involved in the production of functional coagulation factors in the liver, has been shown to be involved in various aspects of physiological and pathological events, including bone metabolism, cardiovascular diseases and tumor biology. The mechanisms and roles of VK are gradually becoming clear. Several novel enzymes involved in the VK cycle were identified and have been shown to be linked to tumorigenesis. The VKs have been shown to suppress liver cancer cell growth through multiple signaling pathways via the transcription factors and protein kinases. A VK2 analog was applied to the chemoprevention of hepatocellular carcinoma (HCC) recurrence after curative therapy and was shown to have beneficial effects, both in the suppression of HCC recurrence and in patient survival. Although a large scale randomized control study failed to demonstrate the suppression of HCC recurrence, a meta-analysis suggested a beneficial effect on the long-term survival of HCC patients. However, the beneficial effects of VK administration alone were not sufficient to prevent or treat HCC in clinical settings. Thus its combination with other anti-cancer reagents and the development of more potent novel VK derivatives are the focus of ongoing research which seeks to achieve satisfactory therapeutic effects against HCC.

Complete response by vitamin K2 analog monotherapy in sorafenib‐failure advanced hepatocellular carcinoma: A case report

“…Therefore, DCP stimulates HCC cell proliferation through the DCP‐Met‐JAK‐STAT3 signaling pathway . It is well known that VK treatment suppresses increases in serum DCP levels . In this case, the patient's DCP level has significantly reduced after treatment with VK2 analog.…”

“…Vitamin K has been reported to show an antitumor effect in several cancer types, including HCC . In clinical practice, there have been some reports that a VK2 analog is beneficial for the prevention of recurrence in HCC patients after curative therapy, although this effect was not confirmed in a large‐scale randomized controlled trial . However, meta‐analyses have shown that VK2 analog administration might reduce the rate of recurrence after 1 year, and improve overall survival in HCC patients as early as 1 year .…”

“…Regarding the antitumor effect of VK, in vitro studies have shown that VK inhibits the growth, invasion, and metastasis of HCC, and induces apoptosis through multiple vsignaling pathways (e.g. protein kinase A, protein kinase C, nuclear factor‐kappa B, signal transducer and activator of transcription (STAT), steroid and xenobiotic receptor, and mitogen‐activated protein kinase pathways) . Des‐γ‐carboxy prothrombin, a well‐known tumor marker of HCC, is itself a growth factor and an angiogenesis‐enhancing factor in HCC .…”

“…Vitamin K2 analogs are also reported to be beneficial to prevent the development of hepatocellular carcinoma (HCC) recurrence after curative treatment . However, the VK2 analogs in current use do not appear to show dramatic antitumor effects when administered alone . Moreover, there have been only a few reports that VK2 analog monotherapy leads to good antitumor responses.…”

Enhanced Intracellular Delivery and Improved Antitumor Efficacy of Menaquinone-4

“…Over the last decade, many reports have shown that MK-4 has antioncogenic effects within various cancer cell lines, including leukemia, lung cancer, ovarian cancer, prostate cancer, and hepatocellular carcinoma (HCC) [3][4][5][6]. Specifically, numerous articles describe the effects of MK-4 against HCC.…”