Growth Inhibition of Hepatoma Cells Induced by Vitamin K and Its Analogs

Abstract

Congeners of vitamin K are known to inhibit cell growth, although the precise mechanisms of growth inhibition are not well understood. To investigate the mechanisms involved, we synthesized several vitamin K analogs and examined their growth inhibitory activities for a human hepatoma cell line (Hep3B). The analogs included 2-methyl-1,4-naphthoquinone and trimethyl-benzoquinone, with and without aliphatic side chains at position 3. The side chains were all-carbon, thioethers, or O-ethers. Growth inhibition was potent in the compounds with short chains. The presence of a sulfur (thioether) or oxygen atom (O-ether) at the site of attachment of the side chain to the ring potentiated the activity. Apoptotic cell death was induced by the potent growth inhibitory compounds at low concentrations (20-60 microM), whereas necrotic cell death followed treatment with the same compounds at high concentrations. Expression of c-myc, which is thought to be associated with apoptosis, was increased by most of the compounds tested. Both reduced glutathione and cysteine almost completely abrogated the growth inhibitory effects of the thioether analogs as well as of vitamin K3. The effect of glutathione was less prominent for the all-carbon and O-ether analogs, and cysteine had no effect on these analogs. Catalase and deferoxamine mesylate had no significant effect on the thioether analogs, although they showed partial antagonistic effects on the growth inhibition of vitamin K3 and the all-carbon and O-ether analogs. Other non-thiol antioxidants tested had no effect on any of the analogs. Our results indicated that vitamin K-related quinoid compounds cause growth inhibition and both apoptotic and necrotic cell death and that the effects may be mediated by interaction at position 3 of their quinoid nuclei with cellular thiols.

Stathmin Mediates Hepatocyte Resistance to Death from Oxidative Stress by down Regulating JNK

“…At the lower 40 µM menadione concentration the levels of apoptosis and necrosis were significantly increased in knockdown cells but death was primarily apoptotic ( Figure 3d ). At the higher 50 µM menadione concentration, cell death in siStath cells was overwhelmingly necrotic ( Figure 3d ), reflecting the ability of higher levels of oxidant stress to convert apoptosis to death by necrosis [24] , including that induced by menadione [41] . Consistent with the fluorescence microscopy findings of apoptosis, caspase 3 and 7 activation, as determined by the appearance of the cleaved, active forms of these proteins on immunoblots, increased in siStath cells with 40 µM menadione treatment ( Figure 3e ).…”

Cysteine 81 Is Critical for the Interaction of S100A4 and Myosin-IIA

“…25,26 As S100A4 contains two solvent accessible cysteine residues (Cys81 and Cys86) in the predicted target binding cleft, 27 we considered that NSC 95397 and associated analogues might disrupt the S100A4/myosin-IIA interaction due to a similar covalent modification of S100A4. To evaluate potential covalent modification of S100A4, we used mass spectrometry techniques.…”

Pankiller effect of prolonged exposure to menadione on glioma cells: potentiation by vitamin C

“…mouse or rat liver tumors, glioma, melanoma and neuroblastoma, cells [1, 2], human glioma [3], hepatoma cells [4] and urologic tumors [5]. Moreover, a potentiation of radiotherapy by vitamin K has been shown [2] as well as a synergistic effect when given in combination with other anti-tumor agents [6].…”