Tumor cell growth inhibition and extracellular signal-regulated kinase (ERK) phosphorylation by novel K vitamins.
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.
Osada
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Starzl Transplantation Institute, University of Pittsburgh, PA 15213, USA. string@cc.gifu-u.ac.jp
Osada
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Carr
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D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011233:Precipitin Tests; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014812:Vitamin K / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*
C446520:2-(2-hydroxyethylsulfanyl)-3-methyl-1,4-naphthoquinone; C446518:2-(2-hydroxyethylsulfanyl)-3-methyl-5-acetylamino-1,4-naphthoquinone; C446519:2-(2-hydroxyethylsulfanyl)-3-methyl-5-nitro-1,4-naphthoquinone; D000975:Antioxidants; D013438:Sulfhydryl Compounds; D014812:Vitamin K; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases