5-Benzylidene-3,4-dihalo-furan-2-one derivatives inhibit human leukemia cancer cells through suppression of NF-κB and GSK-3β
It has been demonstrated that PPARγ agonists effectively inhibit proliferation, metastasis as well as
induce apoptosis in human cancer cell lines. In this study, twenty-two rosiglitazone analogues, 5-benzylidene-3,4-
dihalo-furan-2-one derivatives, which have been identified as PPARγ agonists in our previous work, were evaluated
for their antitumor effects. Among these compounds, (Z)-3,4-dibromo-5-(3-methoxy-4-((3,5,6-trimethylpyrazin-2-
yl)methoxy)benzylidene)furan-2(5H)-one (6w) shows the best antitumor activity, especially against the leukemia
cell line U937, resulting in significant cytotoxicity, increased apoptosis and changes in mitochondrial membrane
potential. Up-regulation of pro-apoptosis-associated proteins (Bax, caspase-3 and caspase-9) and cleaved PARP as
well as down-regulation of anti-apoptosis protein Bcl-2 are observed in 6w-treated U937 cells. It was shown that the
antitumor effect of 6w stems from its ability to inhibit the PPARγ-dependent expression of NF-κB and GSK-3β.
Keywords: Antitumor, GSK-3β, leukemia, NF-κB, PPARγ agonist.
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