Chapters authored
Enhanced Intracellular Delivery and Improved Antitumor Efficacy of Menaquinone-4
Hepatocellular carcinoma (HCC) is a major malignant tumor type that occurs globally. HCC incidence is increasing, especially in Asian countries. Despite many therapeutic approaches, the long-term prognosis of HCC remains poor because of frequent recurrence due to intrahepatic metastasis or multicentric carcinogenesis. Therefore, it is necessary to develop effective and safe chemopreventive agents to improve the prognosis of HCC. Menaquinone-4 (MK-4) has a suppressive effect on HCC, but cellular delivery is poor. We hypothesized that effective cellular delivery of menahydroquinone-4 (MKH), a fully reduced form of MK-4, would regulate HCC growth and metastasis. We developed a bioreductive activation-independent delivery system with the N,N-dimethylglycine ester of MKH (MKH-bis-DMG) to deliver MKH to HCC cells without any bioreductive processing of MK-4. MKH-bis-DMG inhibited the proliferation of both DCP-positive and DCP-negative HCC cell lines in a time- and dose-dependent manner via G1/S cell-cycle arrest. We assessed the effect of MKH-derivatives on HCC metastasis using a mouse model of spleen-liver metastasis. The mean tumor hepatic replacement area of MKH-bis-DMG treated mice was significantly less than that of untreated mice. In conclusion, MKH-bis-DMG may be beneficial as a chemopreventive agent for recurrent HCC.
Part of the book: Vitamin K2
Overcoming the Photochemical Problem of Vitamin K in Topical Application
Topical application of vitamin K is beneficial in the treatment of various skin pathologies. However, its delivery to the skin is hampered by the photo-instability and phototoxicity of vitamin K (quinone form). Indeed, topical use of vitamin K is regulated in Europe owing to the photosensitive properties of this molecule. Here, we discuss the suitability of ester derivatives of vitamin K hydroquinone (VKH), the active form of vitamin K, for topical applications. Notably, VKH derivatives have the potential to overcome the photo-instability and phototoxicity problem of vitamin K and act as VKH prodrugs, as demonstrated in HaCaT human keratinocytes. Thus, VKH prodrug is a promising strategy for topical application of vitamin K without the need for special protection from light.
Part of the book: Vitamin K