Tumor cell growth inhibition and extracellular signal-regulated kinase (ERK) phosphorylation by novel K vitamins.

Abstract

2-(2-hydroxy-ethylsulfanyl)-3-methyl-1,4-naphthoquinone or CPD-5, a K vitamin analog, was previously indicated to be a potent growth inhibitor for Hep 3B hepatoma cells in vitro. Here, we show that CPD-5 and two newly synthesized analogs, 2-(2-hydroxy-ethylsulfanyl)-3-methyl-5- nitro-1,4-naphthoquinone (PD-37) and 2-(2-hydroxy-ethylsulfanyl)-3- methyl-5-acetylamino-1,4-naphthoquinone (PD-42), are potent growth inhibitors of 13 different human cancer cell lines, with IC50 values in the range of 3-54 microM. Phospho-ERK was induced by each of three K vitamin analogs in every cell line in a dose-dependent manner, at growth inhibitory doses. ERK phosphorylation and growth inhibitory effects were strongly correlated, with p=0.0080 for CPD-5, p=0.0076 for PD-37 and p=0.0251 for PD-42. The induction of phospho-ERK and growth inhibition were antagonized by thiol-containing anti-oxidants, but not by catalase, consistent with a possible arylating mechanism. The data show a novel class of growth inhibitors with a wide spectrum of action that induces ERK hyper-phosphorylation, as a possible new growth inhibitory feature.

• Authors: S Osada, K Osada, B I Carr
• Journal: Journal of molecular biology (J Mol Biol) Vol. 314 Issue 4 Pg. 765-72 (Dec 07 2001) ISSN: 0022-2836 [Print] Netherlands
• PMID: 11733995 (Publication Type: Journal Article)
• Copyright: Copyright 2001 Academic Press.

Chemical References

• 2-(2-hydroxyethylsulfanyl)-3-methyl-1,4-naphthoquinone
• 2-(2-hydroxyethylsulfanyl)-3-methyl-5-acetylamino-1,4-naphthoquinone
• 2-(2-hydroxyethylsulfanyl)-3-methyl-5-nitro-1,4-naphthoquinone
• Antioxidants
• Sulfhydryl Compounds
• Vitamin K
• ErbB Receptors
• Proto-Oncogene Proteins c-met
• Mitogen-Activated Protein Kinases
• Protein Tyrosine Phosphatases

Topics

• Antioxidants (pharmacology)
• Blotting, Western
• Cell Division (drug effects)
• Dose-Response Relationship, Drug
• ErbB Receptors (metabolism)
• Humans
• Inhibitory Concentration 50
• Liver Neoplasms (metabolism, pathology)
• Mitogen-Activated Protein Kinases (metabolism)
• Neoplasms (metabolism, pathology)
• Phosphorylation (drug effects)
• Precipitin Tests
• Protein Tyrosine Phosphatases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-met (metabolism)
• Sulfhydryl Compounds (pharmacology)
• Tumor Cells, Cultured
• Vitamin K (analogs & derivatives, antagonists & inhibitors, chemistry, pharmacology)