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.