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, Gautam Sethi

Research output: Contribution to journalArticlepeer-review

77 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)12831-12842
Number of pages12
JournalOncotarget
Volume8
Issue number8
DOIs
Publication statusPublished - 2017
Externally publishedYes

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