• 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  • 2 Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore
  • 3 Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 4 School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, India
  • 5 Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia,
  • 6 Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA, Australia
Oncotarget, 2017 Feb 21;8(8):12831-12842.
PMID: 28086233 DOI: 10.18632/oncotarget.14606


A prior screening programme carried out using MTT assay by our group identified a series of novel benzimidazole derivatives, among which Methyl 2-(5-fluoro-2-hydroxyphenyl)-1H- benzo[d]imidazole-5-carboxylate (MBIC) showed highest anticancer efficacy compared to that of chemotherapeutic agent, cisplatin. In the present study, we found that MBIC inhibited cell viability in different hepatocellular carcinoma (HCC) cell lines without exerting significant cytotoxic effects on normal liver cells. Annexin V-FITC/PI flow cytometry analysis and Western blotting results indicated that MBIC can induce apoptosis in HCC cells, which was found to be mediated through mitochondria associated proteins ultimately leading to the activation of caspase-3. The exposure to MBIC also resulted in remarkable impairment of HCC cell migration and invasion. In addition, treatment with MBIC led to a rapid generation of reactive oxygen species (ROS) and substantial activation of c-Jun-N-terminal kinase (JNK). The depletion of ROS by N-Acetyl cysteine (NAC) partially blocked MBIC-induced apoptosis and JNK activation in HCC cells. Finally, MBIC significantly inhibited tumor growth at a dose of 25 mg/kg in an orthotopic HCC mouse model. Taken together, these results demonstrate that MBIC may inhibit cell proliferation via ROS-mediated activation of the JNK signaling cascade in HCC cells.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.