H32, a non-quinone sulfone analog of vitamin K3, inhibits human hepatoma cell growth by inhibiting Cdc25 and activating ERK

Siddhartha Kar, Meifang Wang, Wook Ham Seung, Brian I. Carr

Research output: Contribution to journalArticle

Abstract

We previously synthesized a K-vitamin derivative, Cpd 5, which was a potent growth inhibitor of human tumor cells, including Hep3B hepatoma cells. However, being a quinone compound, Cpd 5 has the potential for generating toxic reactive oxygen species (ROS). We therefore synthesized a nonquinone sulfone derivative, H32, which has a sufone group substituting the quinone. The IC50 of H32 for Hep3B cells was found to be 2.5 μM, which was 2.5 and 3.2 times more potent than Cpd 5 and vitamin K3 respectively. It induced apoptosis in Hep3B cells but did not generate ROS when compared to Cpd 5. Interestingly, under similar culture conditions, normal rat hepatocytes were 14-fold more and 7-fold more resistant to the growth inhibitory effects of H32 than Hep3B and PLC/ PRF5 cells respectively. H32 preferentially inhibited the activities of the cell cycle controlling Cdc25A phosphatase likely by binding to its catalytic cysteine. As a consequence, it induced inhibitory tyrosine phosphorylation of the Cdc25 substrate kinases Cdk2 and Cdk4 in Hep3B cells and the cells undergo an arrest in the G1 phase of the cell cycle. H32 also induced persistent phosphorylation of the MAPK protein ERK1/2, but marginal JNK1/2 and p38 phosphorylation. The ERK inhibitor U0126, added at least 30 min prior to H32, antagonized the growth inhibition induced by H32. However, the JNK and p38 inhibitors, JNKI-II and SB203580, were not able to antagonize H32 induced growth inhibition. Thus, H32 differentially inhibited growth of normal and liver tumor cells by preferentially inhibiting the actions of Cdc25 phosphatases and inducing persistent ERK phosphorylation.

Original languageEnglish
Pages (from-to)1340-1347
Number of pages8
JournalCancer Biology and Therapy
Volume5
Issue number10
Publication statusPublished - Oct 2006

Fingerprint

Vitamin K 3
Sulfones
Hepatocellular Carcinoma
Growth
cdc25 Phosphatases
Phosphorylation
Reactive Oxygen Species
Cell Cycle
Activity Cycles
Growth Inhibitors
Vitamin K
Poisons
G1 Phase
Inhibitory Concentration 50
Cysteine
Tyrosine
Hepatocytes
Neoplasms
Phosphotransferases
Apoptosis

Keywords

  • Cdc25 inhibition
  • ERK phosphorylation
  • Hepatoma cells
  • Small molecule inhibitor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

H32, a non-quinone sulfone analog of vitamin K3, inhibits human hepatoma cell growth by inhibiting Cdc25 and activating ERK. / Kar, Siddhartha; Wang, Meifang; Seung, Wook Ham; Carr, Brian I.

In: Cancer Biology and Therapy, Vol. 5, No. 10, 10.2006, p. 1340-1347.

Research output: Contribution to journalArticle

Kar, Siddhartha ; Wang, Meifang ; Seung, Wook Ham ; Carr, Brian I. / H32, a non-quinone sulfone analog of vitamin K3, inhibits human hepatoma cell growth by inhibiting Cdc25 and activating ERK. In: Cancer Biology and Therapy. 2006 ; Vol. 5, No. 10. pp. 1340-1347.
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