Enhanced antitumor effects of novel intracellular delivery of an active form of menaquinone-4, menahydroquinone-4, into hepatocellular carcinoma.

Abstract

Reduced cellular uptake of menaquinone-4 (MK-4), a vitamin K2 homolog, in human hepatocellular carcinoma (HCC) limits its usefulness as a safe long-term antitumor agent for recurrent HCC and produces des-γ-carboxy prothrombin (DCP). We hypothesized that effective delivery of menahydroquinone-4 (MKH), the active form of MK-4 for γ-glutamyl carboxylation, into HCC cells is critical for regulating HCC growth, and may enable it to be applied as a safe antitumor agent. In this study, we verified this hypothesis using menahydroquinone-4 1,4-bis-N,N-dimethylglycinate hydrochloride (MKH-DMG), a prodrug of MKH, and demonstrated its effectiveness. Intracellular delivery of MKH and subsequent growth inhibition of PLC/PRF/5 and Hep3B (DCP-positive) and SK-Hep-1 (DCP-negative) cells after MKH-DMG administration were determined and compared with MK-4. The activity of MKH-DMG against tumor progression in the liver alongside DCP formation was determined in a spleen-liver metastasis mouse model. MKH-DMG exhibited greater intracellular delivery of MKH in vitro (AUC0-72 hour of MKH) and increased growth-inhibitory activity against both DCP-positive and DCP-negative HCC cell lines. The phenomena of MKH delivery into cells in parallel with simultaneous growth inhibition suggested that MKH is the active form for growth inhibition of HCC cells. Cell-cycle arrest was determined to be involved in the growth inhibition mechanisms of MKH-DMG. Furthermore, MKH-DMG showed significant inhibition of tumor progression in the liver, and a substantial decrease in plasma DCP levels in the spleen-liver metastasis mouse model. Our results suggest that MKH-DMG is a promising new candidate antitumor agent for safe long-term treatment of HCC.

• Authors: Shuichi Setoguchi, Daisuke Watase, Kazuhisa Matsunaga, Misa Matsubara, Yohei Kubo, Mariko Kusuda, Nami Nagata-Akaho, Munechika Enjoji, Manabu Nakashima, Morishige Takeshita, Yoshiharu Karube, Jiro Takata
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 8 Issue 2 Pg. 129-38 (Feb 2015) ISSN: 1940-6215 [Electronic] United States
• PMID: 25416411 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Hydroquinones
• Vitamin K 2
• menahydroquinone-4

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Carcinoma, Hepatocellular (drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chromatography, Liquid
• Disease Models, Animal
• Flow Cytometry
• Humans
• Hydroquinones (pharmacology)
• Intracellular Space (metabolism)
• Liver Neoplasms (drug therapy)
• Male
• Mass Spectrometry
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Vitamin K 2 (analogs & derivatives, pharmacology)