A novel benzimidazole derivative, MBIC inhibits tumor growth and promotes apoptosis via activation of ROS-dependent JNK signaling pathway in hepatocellular carcinoma
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Résumé
// Xiaoyun Dai 1, * , Lingzhi Wang 1, 2, * , Amudha Deivasigamni 3, * , Chung Yeng Looi 4 , Chandrabose Karthikeyan 5 , Piyush Trivedi 5 , Arunachalam Chinnathambi 6 , Sulaiman Ali Alharbi 6 , Frank Arfuso 7 , Arunasalam Dharmarajan 7 , Boon Cher Goh 1, 2, 8 , Kam Man Hui 3, 9, 10, 11 , Alan Prem Kumar 1, 2, 12, 13 , Mohd Rais Mustafa 4 , Gautam Sethi 1, 6, 14 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 2 Cancer Science Institute of Singapore, Centre for Translational Medicine, Singapore 3 Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 4 Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 5 School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, India 6 Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia, 7 Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA, Australia 8 Department of Haematology-Oncology, National University Health System, Singapore 9 Institute of Molecular and Cell Biology, A*STAR, Biopolis Drive Proteos, Singapore 10 Cancer and Stem Cell Biology Program, Duke–National University of Singapore Graduate Medical School, Singapore 11 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 12 Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth WA, Australia 13 Department of Biological Sciences, University of North Texas, Denton, Texas, USA 14 School 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: phcgs@nus.edu.sg Kam Man Hui, email: cmrhkm@nccs.com.sg Mohd Rais Mustafa, email: rais@nm.edu.my Alan Prem Kumar, email: csiapk@nus.edu.sg Keywords: MBIC, HCC, JNK, ROS, apoptosis Received: July 27, 2016 Accepted: December 15, 2016 Published: January 12, 2017 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.
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Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découle