Enhanced Intracellular Delivery and Improved Antitumor Efficacy of Menaquinone-4

Abstract

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.

The aerobic respiratory chain of Pseudomonas aeruginosa cultured in artificial urine media: Role of NQR and terminal oxidases

“…The activity of other dehydrogenases was measured with 10 mM D, L-malate, 10 mM L-lactate, 10 mM glucose or 0.3% ethanol. Quinol oxidase activity was assessed with 50 μM ubiquinone-1 (2,3-Dimethoxy-5-methyl-6-(3-methyl-2-butenyl)-1,4-benzoquinone, Sigma-Aldrich) or menaquinone-2 (2-(3,7-dimethyl-2,6-octadienyl)-3-methyl-1,4-Naphthoquinone, Sigma-Aldrich) in the presence of 500 μM DTT, which readily reduces these quinones [43][44][45][46]. The activity of cytochrome c oxidases was tested with the artificial redox couple 100 μM TMPD + and 5 mM ascorbic acid.…”