Research Papers:

A novel benzimidazole derivative, MBIC inhibits tumor growth and promotes apoptosis via activation of ROS-dependent JNK signaling pathway in hepatocellular carcinoma

Xiaoyun Dai, Lingzhi Wang, Amudha Deivasigamni, Chung Yeng Looi, Chandrabose Karthikeyan, Piyush Trivedi, Arunachalam Chinnathambi, Sulaiman Ali Alharbi, Frank Arfuso, Arunasalam Dharmarajan, Boon Cher Goh, Kam Man Hui, Alan Prem Kumar, Mohd Rais Mustafa and Gautam Sethi _

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Oncotarget. 2017; 8:12831-12842. https://doi.org/10.18632/oncotarget.14606

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Xiaoyun Dai1,*, Lingzhi Wang1,2,*, Amudha Deivasigamni3,*, Chung Yeng Looi4, Chandrabose Karthikeyan5, Piyush Trivedi5, Arunachalam Chinnathambi6, Sulaiman Ali Alharbi6, Frank Arfuso7, Arunasalam Dharmarajan7, Boon Cher Goh1,2,8, Kam Man Hui3,9,10,11, Alan Prem Kumar1,2,12,13, Mohd Rais Mustafa4, Gautam Sethi1,6,14

1Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

2Cancer Science Institute of Singapore, Centre for Translational Medicine, Singapore

3Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore

4Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

5School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, India

6Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia,

7Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA, Australia

8Department of Haematology-Oncology, National University Health System, Singapore

9Institute of Molecular and Cell Biology, A*STAR, Biopolis Drive Proteos, Singapore

10Cancer and Stem Cell Biology Program, Duke–National University of Singapore Graduate Medical School, Singapore

11Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

12Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth WA, Australia

13Department of Biological Sciences, University of North Texas, Denton, Texas, USA

14School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA, Australia

*These authors contributed equally to this work

Correspondence to:

Gautam Sethi, email: [email protected]

Kam Man Hui, email: [email protected]

Mohd Rais Mustafa, email: [email protected]

Alan Prem Kumar, email: [email protected]

Keywords: MBIC, HCC, JNK, ROS, apoptosis

Received: July 27, 2016     Accepted: December 15, 2016     Published: January 12, 2017


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.

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