Carboxylic Derivatives of Vitamin K2 Inhibit Hepatocellular Carcinoma Cell Growth through Caspase/Transglutaminase-Related Signaling Pathways

Abstract

Summary Chemoprevention of hepatocellular carcinoma (HCC) is one of the most challenging aspects of medical research. Vitamin K2 (VK2) has been suggested for its chemopreventive role in treatment of HCC, while inconsistent results in clinical trials have been reported. The present study was initiated to add to our insight into the anti-HCC cell proliferative effect of VK2 and its derivatives from a viewpoint of chemical structure. No significant effect was observed with original VK2, while VK2 derivatives bearing both isoprene units and a carboxyl-terminated side chain dose-dependently inhibited the growth of HCC cells without affecting normal liver cells. Loss-of-function analyses revealed that the anti-HCC cell activity by the VK2 derivatives was not mediated by a VK2 binding protein Bcl-2 homologous antagonist/killer (Bak) but rather associated with caspase/transglutaminase-related signaling pathways. Further studies on the carboxylic derivatives of VK2 bearing isoprene structural units introduced in this study might shed new light on the systemic treatment and prevention of HCC.

Prevention of hepatocellular carcinoma by targeting MYCN-positive liver cancer stem cells with acyclic retinoid

“…1 F ). In contrast, the vitamin K2 analog SVK30 with an ACR-like structure containing three isoprene residues in its C-terminal side chain, exhibited HCC-selective cell-killing activity ( 24 ) and inhibited MYCN expression in JHH7 cells ( Fig. S1 C ).…”

Long-Chain Metabolites of Vitamin E: Metabolic Activation as a General Concept for Lipid-Soluble Vitamins?

“…Data on anti-cancerogenic effects of vitamin K metabolites, however, are sparse. Merely synthetic carboxylic derivatives of menaquinone with different side-chain lengths have been studied [ 89 ]. The biologically most abundant 5-carbon carboxylic acid metabolite (K acid 2) was not included in this study and the 7-carbon carboxylic acid metabolite (K acid 1) was the structure with the shortest side-chain.…”

“…Conversely, menaquinone itself was completely ineffective, showing nicely that the introduction of a carboxy function activates the compound. Blocking of the effects with chemical antagonists suggested that the derivatives act through caspase/transglutaminase-related signaling [ 89 ]. The above mentioned disruption of mitochondrial function by the LCMs of vitamin E has also been described for the metabolites of vitamin A [ 90 ], and induction of apoptosis by 1,25(OH) 2 D 3 via mitochondrial pathways (e.g., via B-cell lymphoma (BCL)-2 and BCL-xL) in breast, colon and prostate cancer cells are also known [ 87 ].…”

Transglutaminase 2 as a Marker for Inflammation and Therapeutic Target in Sepsis

“…Following the co-culture of Candida albicans and hepatocytes, TG2 translocates into the nucleus and is activated by ROS generated by Candida albicans [76]. The induction of TG2 was also involved in the cell death induced by retinoids and fatty acids in hepatic cells [77][78][79]. In the LPS-induced sepsis mouse model, TG2 in the hepatic macrophages was activated, and the inhibition of TG2 activation prevented LPS-induced hepatic damage, as indicated by the serum level of ALT, which is a well-established indicator of hepatocyte cell death [22].…”