Growth inhibition of hepatoma cells induced by vitamin K and its analogs

Y. Nishikawa, B. I. Carr, M. Wang, S. Kar, F. Finn, P. Dowd, Z. B. Zheng, J. Kerns, S. Naganathan

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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- benxoquinone, 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 μM), 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.

Original languageEnglish
Pages (from-to)28304-28310
Number of pages7
JournalJournal of Biological Chemistry
Volume270
Issue number47
DOIs
Publication statusPublished - 1995

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Vitamin K
Hepatocellular Carcinoma
Sulfides
Vitamin K 3
Growth
Cell death
Ether
Carbon
Cell Death
Glutathione
Cysteine
Deferoxamine
Ethers
Cell growth
Sulfur
Sulfhydryl Compounds
Catalase
Human Activities
Antioxidants
Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

Nishikawa, Y., Carr, B. I., Wang, M., Kar, S., Finn, F., Dowd, P., ... Naganathan, S. (1995). Growth inhibition of hepatoma cells induced by vitamin K and its analogs. Journal of Biological Chemistry, 270(47), 28304-28310. https://doi.org/10.1074/jbc.270.47.28304

Growth inhibition of hepatoma cells induced by vitamin K and its analogs. / Nishikawa, Y.; Carr, B. I.; Wang, M.; Kar, S.; Finn, F.; Dowd, P.; Zheng, Z. B.; Kerns, J.; Naganathan, S.

In: Journal of Biological Chemistry, Vol. 270, No. 47, 1995, p. 28304-28310.

Research output: Contribution to journalArticle

Nishikawa, Y, Carr, BI, Wang, M, Kar, S, Finn, F, Dowd, P, Zheng, ZB, Kerns, J & Naganathan, S 1995, 'Growth inhibition of hepatoma cells induced by vitamin K and its analogs', Journal of Biological Chemistry, vol. 270, no. 47, pp. 28304-28310. https://doi.org/10.1074/jbc.270.47.28304
Nishikawa, Y. ; Carr, B. I. ; Wang, M. ; Kar, S. ; Finn, F. ; Dowd, P. ; Zheng, Z. B. ; Kerns, J. ; Naganathan, S. / Growth inhibition of hepatoma cells induced by vitamin K and its analogs. In: Journal of Biological Chemistry. 1995 ; Vol. 270, No. 47. pp. 28304-28310.
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AU - Naganathan, S.

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AB - 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- benxoquinone, 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 μM), 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.

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