Abstract
Hepatocellular carcinoma (HCC) shows poor prognosis owing to its very frequent recurrence even after curative treatment. Thus, an effective and safe long-term chemopreventive agent is strongly in demand. Menahydroquinone-4 (MKH) is an active form of menaquinone-4 (MK-4, vitamin K2) that is involved in the synthesis of vitamin K-dependent proteins in the liver. We hypothesized that efficient delivery of MKH might be critical to regulate HCC proliferation. The discovery of a suitable prodrug targeting HCC in terms of delivery and activation could reduce the clinical dose of MK-4 and maximize efficacy and safety. We previously showed that MKH dimethylglycinate (MKH-DMG) enables effective delivery of MKH into HCC cells and exhibits strong antitumor effects compared with MK-4. In this study, we prepared anionic MKH hemi-succinate (MKH-SUC) and non-ionic MKH acetate (MKH-ACT), in addition to cationic MKH-DMG, and evaluated MKH delivery profiles and antitumor effects in vitro. MKH-SUC showed the highest uptake and the most efficient release of MKH among the examined compounds and exhibited rapid and strong antitumor effects. These results indicate that MKH-SUC might have a good potential as an MKH delivery system for HCC that overcomes the limitations of MK-4 as a clinical chemopreventive agent.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common human malignant tumors in the world
We previously reported that an MKH N,N-dimethylglycine ester prodrug (MKH-DMG) can deliver the active form effectively into both Des-γ-carboxy prothrombin (DCP)-positive and -negative
We previously demonstrated that the esterified prodrug of MKH, MKH dimethylglycinate (MKH-DMG), can deliver MKH
Summary
Hepatocellular carcinoma (HCC) is one of the most common human malignant tumors in the world. A vascular endothelial growth factor receptor tyrosine kinase inhibitor, is the first systemic agent to be approved for the treatment of unresectable HCC, and regorafenib and nivolumab have been approved [3,4]. In Japan, lenvatinib has been approved for the first time in the world. These systemic agents are excellent developments in the treatment of HCC; these agents are only applicable for unresectable HCC, and strong adverse effects, such as skin and liver toxicities, hemorrhage and hypertension, are sometimes observed [1,3]. Less toxic and effective agents for HCC at an earlier stage are needed
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