Uptake mechanism of prodrug of an active form of vitamin K2 in hepatocellular carcinoma cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K15288
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47050:Environmental and natural pharmaceutical resources-related
• Research Institution: Fukuoka University
• Principal Investigator: SETOGUCHI Shuichi 福岡大学, 薬学部, 講師 (80826032)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: prodrug / uptake / vitamin K / hepatocellular carcinoma

Outline of Final Research Achievements

The dimethyl glycine prodrug of MKH, an active form of vitamin K2, (MKH-DMG) could deliver MKH into hepatocellular carcinoma (HCC) cells via efficient cellular uptake, and exhibited strong antitumor effects. The specific uptake of MKH prodrug is critical for efficient delivery to HCC cells; however, the uptake mechanism remains unclear. To elucidate the underlying mechanism, we determined the kinetic profiles of the intracellular MKH prodrug in HCC cell lines. Cooling temperature and ezetimibe (NPC1L1 transporter inhibitor) could reduce the cellular uptake of MKH-DMG, indicating active transport via NPC1L1. However, the effect of plasmid NPC1L1 on MKH-DMG uptake was not observed. NPC1L1 expression may affect uptake of vitamin K only on intestinal model cells and ezetimibe may inhibit endocytosis of MKH-DMG into HCC cell lines and HEK293.

Free Research Field

Drug Delivery System

Academic Significance and Societal Importance of the Research Achievements

肝細胞癌（HCC）は予後が極めて悪いがんの一つであり、分子標的薬が登場した現在でも、より安全で安価な化学療法薬が求められている。ビタミンK2は骨粗鬆症の治療薬としての実績から安全な抗HCC薬候補として今なお期待されている。我々はビタミンK依存性タンパク質生合成の活性体である還元型ビタミンK2（MKH）のカチオン性プロドラッグが高い細胞増殖抑制効果と効率的なMKH送達を示すことを明らかにしている。一方、当該プロドラッグの効率的な効果発現はHCC細胞内への効率的な取込みが鍵であり、もしHCC特異的な取込みが観察されればより安全な候補化合物として期待できる。