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Front. Oncol. | doi: 10.3389/fonc.2018.00042

Novel 1, 3, 4-Oxadiazole Induces Anticancer Activity by Targeting NF-κB in Hepatocellular Carcinoma Cells

 Chakrabhavi D. Mohan1*,  Nirvanappa C. Anilkumar2, Shobith Rangappa3,  Muthu K. Shanmugam4, Atanu Bhattacharjee5, Gautam Sethi4,  Basappa Basappa2, 6* and Kanchugarakoppal S. Rangappa6
  • 1Department of Studies in Molecular Biology, University of Mysore, India
  • 2Bangalore University, India
  • 3Adichunchanagiri Institute for Molecular Medicine, India
  • 4National University of Singapore, Singapore
  • 5North Eastern Hill University, India
  • 6University of Mysore, India

Aberrant activation of NF-κB is linked with the progression of human malignancies including hepatocellular carcinoma (HCC) and blockade of NF-κB signalling could be a potential target in the treatment of several cancers. Therefore, designing of novel small molecule inhibitors that target NF-κB activation of prime importance in the treatment of several cancers. In the present work, we report the synthesis of series of 1,3,4-oxadiazoles, investigated their anticancer potential against HCC cells and identified 2-(3-chlorobenzo[b]thiophen-2-yl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (CMO) as the lead compound. Further, we examined the effect of CMO on cell cycle distribution (flow cytometry), apoptosis (annexin V-PI-FITC staining) and phosphorylation of NF-κB signalling pathway proteins (IκB and p65) in HCC cells. We found that CMO induced antiproliferative effect in dose- and time-dependent manner. Also, CMO significantly increased the percentage of sub-G1 cell population and induced apoptosis. Furthermore, CMO found to decrease the phosphorylation of IκB (Ser 32) in the cytoplasmic extract and p65 (Ser 536) in the nuclear extract of HCC cells. It also abrogated the DNA binding ability and transcriptional activity of NF-κB. CMO induced the cleavage of PARP and caspase-3 in a time-dependent manner. In addition, transfection with p65 siRNA blocks CMO induced caspase-3/7 activation. Molecular docking analysis revealed that CMO interacts with interface of p50 and p65 proteins. Thus, we are reporting CMO as an inhibitor of NF-κB signalling pathway.

Keywords: Oxadiazoles, NF-κB, Hepatocellular Carcinoma, Apoptosis, anticancer

Received: 25 Sep 2017; Accepted: 08 Feb 2018.

Edited by:

Zhi Sheng, Virginia Tech, United States

Reviewed by:

Harikumar KB, Rajiv Gandhi Centre for Biotechnology, India
Yun Dai, Virginia Commonwealth University, United States  

Copyright: © 2018 Mohan, Anilkumar, Rangappa, Shanmugam, Bhattacharjee, Sethi, Basappa and Rangappa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Chakrabhavi D. Mohan, University of Mysore, Department of Studies in Molecular Biology, Mysore, India, cd.mohan@yahoo.com
Dr. Basappa Basappa, Bangalore University, Bangalore, India, salundibasappa@gmail.com