Journal
FRONTIERS IN PHARMACOLOGY
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2018.01125
Keywords
oxazines; anticancer; NF-kappa B; hepatocellular carcinoma; apoptosis
Categories
Funding
- Council of Scientific and Industrial Research [02(0291) 17/EMR-II]
- Department of Biotechnology [BT/PR/8064/BID/7/441/2013]
- Vision Group on Science and Technology, Government of Karnataka
- National Medical Research Council of Singapore
- NCIS Yong Siew Yoon Research Grant
- National Research Foundation Singapore
- Singapore Ministry of Education under its Research Centers of Excellence initiative to Cancer Science Institute of Singapore
- National University of Singapore
- University Grants Commission, Government of India
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Hepatocellular carcinoma (HCC) is a fatal disease and ranked fifth in cancer related mortality. Persistent activation of NF-kappa B is responsible for the oncogenesis, metastasis, tumor evasion, anti-apoptosis, angiogenesis and proliferation in HCC. Therefore, designing of chemically novel, biologically potent small molecules that target NF-kappa B signaling cascade have gained prominent clinical interest. Herein we synthesized a novel class of 4-(substituted)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one by reacting 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one with various alkyl halides by using combustion derived bismuth oxide. We evaluated the antiproliferative efficacy of newly synthesized compounds against HCC cells and identified 4-(4-nitrobenzyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (NPO) as lead anticancer agent. In addition, we investigated the effect of NPO on the DNA binding ability of NF-kappa B and NF-kappa B regulated luciferase expression in HCC cells. The results demonstrated that NPO can induce significant growth inhibitory effects in HepG2, HCCLM3 and Huh-7 cells in dose and time-dependent manner. Interestingly, NPO induced significant downregulation in p65 DNA binding ability, p65 phosphorylation and subsequent expression of NF-kappa B dependent luciferase gene expression in diverse HCC cell lines. Further, in silico docking analysis suggested that NPO can show direct physical interaction with NF-kappa B. Finally, NPO was found to significantly abrogate tumor growth at a dose of 50 mg/kg in an orthotopic mouse model. Thus, we report the potential anticancer effects of NPO as a novel inhibitor of NF-kappa B signaling pathway in HCC.
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