Novel synthetic coumarins that targets NF-κB in Hepatocellular carcinoma

Abstract

a b s t r a c tHepatocellular carcinoma (HCC) is the fifth most common malignant tumor worldwide, and is the third most common cause of cancer related death. Constitutive activation of NF-jB is the underlying mechanism behind tumorigenesis and this protein regulates the expression of genes involved in proliferation, survival, drug resistance, angiogenesis and metastasis. The design of inhibitors which suppress NF-jB activation is therefore of great therapeutic importance in the treatment of HCC. In this study, we investigated the effect of newly synthesized coumarin derivatives against HCC cells, and identified (7-Carbethoxyamino-2-oxo-2H-chromen-4-yl)methylpyrrolidine-1 carbodithioate (CPP) as lead compound. Further, we evaluated the effect of CPP on the DNA binding ability of NF-jB, CXCL12-induced cell migration and invasion, and the regulated gene products in HCC cells. We found that CPP induced cytotoxicity in three HCC cells in a time and dose dependent manner, and suppressed the DNA binding ability of NF-jB. CPP significantly decreased the CXCL12-induced cell migration and invasion. More evidently, CPP inhibits the expression of NF-jB targeted genes such as cyclin D1, Bcl-2, survivin, MMP12 and C-Myc. Furthermore, the molecular docking analysis suggested that CPP interacts with the p50 binding domain of the p65 subunit, scoring best among the 26 docked coumarin derivatives of this study. Thus, we are reporting CPP as a potent inhibitor of the pro-inflammatory pathway in Hepatocellular carcinoma.Ó 2014 Elsevier Ltd. All rights reserved.Hepatocellular carcinoma (HCC) is the most common form of liver cancer, and is the third most common cause of cancer related mortality. 1 Obesity, hepatitis B or hepatitis C virus infection, consumption of aflatoxin B1, and alcoholic hepatitis are the major risk factors of HCC. 2 The majority of patients with HCC are diagnosed at a late stage of the disease, with therapy limited to only liver transplantation and surgical liver sectioning. Early detection of HCC may contribute to the strengthening of prognosis. 3,4 Nuclear factor kappa B (NF-jB) is an inducible transcription factor present ubiquitously in the cytoplasm of almost all mammalian cells, and was identified by Baltimore and colleagues in 1986. 5 In an unstimulated cell, NF-jB is associated with IjB (inhibitory jB), and resides in the cytoplasm. 6 Different ligands acting upon the receptor result in a cascade of upstream kinases, finally leading to phosphorylation and ubiquitylation of IjB, which is targeted for degradation. NFjB translocates into nucleus and regulates transcription of the genes involved in inflammation. 7 NF-jB is referred to as a double-edged sword by researchers because of its critical role in proper functioning of the immune system, and the possibility that oncogenesis may arise from the slightest change in regulation. 8 Several anti-apoptotic, angiogenic, inflammatory, metastasis-related, and http://dx

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