Abstract
Signal transducer and activator of transcription 3 (STAT3) is a tumorigenic transcription factor that is persistently activated in various human cancers including hepatocellular carcinoma (HCC). Therefore, STAT3 is considered as a prominent target to counteract the uncontrolled proliferation of cancer cells. In the present report, pyrimidine-2,4-diones (N-methyluracil derivatives) (MNK1-MNK14) were synthesized in an ionic liquid (BMIm PF
) medium employing a ligand-free Suzuki-Miyaura cross-coupling process. Among the 14 derivatives, compound MNK8 showed good cytotoxicity towards both the tested cell lines and did not display a toxic effect against normal hepatocytes (LO2). MNK8 significantly increased the Sub-G1 cell count in both cell lines and the cytotoxic effect of MNK8 was found to be mediated through the suppression of constitutive phosphorylation of STAT3
. It also decreased the DNA interaction ability of nuclear STAT3 in HCC cells. MNK8 downregulated the levels of apoptosis-related proteins (such as Bcl-2, cyclin D1, survivin) and increased cleaved caspase-3 inferring the apoptogenic effect of MNK8. It also reduced the CXCL12-triggered cell migration and invasion in in vitro assay systems. Overall, MNK8 has been demonstrated as a new inhibitor of STAT3 signaling cascade in HCC cells.