H32, a non-quinone sulfone analog of vitamin K3, inhibits human hepatoma cell growth by inhibiting Cdc25 and activating ERK.
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 microM, 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.
Kar
Siddhartha
S
Liver Cancer Center, T. E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Wang
Meifang
M
Ham
Seung Wook
SW
Carr
Brian I
BI
D000818:Animals; D006528:Carcinoma, Hepatocellular; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004247:DNA / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D009285:Naphthoquinones / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013450:Sulfones / Q000494:pharmacology*; D024483:Vitamin K 3 / Q000037:antagonists & inhibitors*; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors*
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; C519219:H32 compound; D009285:Naphthoquinones; D013450:Sulfones; D024483:Vitamin K 3; D004247:DNA; D048049:Extracellular Signal-Regulated MAP Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases