N-Substituted Pyrido-1,4-Oxazin-3-Ones Induce Apoptosis of Hepatocellular Carcinoma Cells by Targeting NF-κB Signaling Pathway

• Main Authors: Chakrabhavi Dhananjaya Mohan (Author), Hanumantharayappa Bharathkumar (Author), Dukanya (Author), Shobith Rangappa (Author), Muthu K. Shanmugam (Author), Arunachalam Chinnathambi (Author), Sulaiman Ali Alharbi (Author), Tahani Awad Alahmadi (Author), Atanu Bhattacharjee (Author), Peter E. Lobie (Author), Amudha Deivasigamani (Author), Kam Man Hui (Author), Gautam Sethi (Author), Basappa (Author), Kanchugarakoppal S. Rangappa (Author), Alan Prem Kumar (Author)
• Format: Book
• Published: Frontiers Media S.A., 2018-11-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1663-9812; 10.3389/fphar.2018.01125
• Keywords: oxazines; anticancer; NF-κB; hepatocellular carcinoma; apoptosis; Therapeutics. Pharmacology; RM1-950
• Source: Frontiers in Pharmacology, Vol 9 (2018)

Hepatocellular carcinoma (HCC) is a fatal disease and ranked fifth in cancer related mortality. Persistent activation of NF-κB 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-κB 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-κB and NF-κB 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-κB dependent luciferase gene expression in diverse HCC cell lines. Further, in silico docking analysis suggested that NPO can show direct physical interaction with NF-κB. 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-κB signaling pathway in HCC.