Therapeutic effect of a multi-targeted imidazolium compound in hepatocellular carcinoma
| Autor: | Zhiyuan Ke, Karthikeyan Narayanan, Began Gopalan, Yugen Zhang, Lang Zhuo, Ting Lu |
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| Rok vydání: | 2014 |
| Předmět: |
Male
MAPK/ERK pathway medicine.medical_specialty Carcinoma Hepatocellular Biophysics Mice Nude Antineoplastic Agents Apoptosis Bioengineering Biomaterials Mice Cyclin D1 Cell Line Tumor Internal medicine Survivin medicine Animals Humans Molecular Targeted Therapy Epidermal growth factor receptor Cyclin Mitogen-Activated Protein Kinase 1 Mice Inbred BALB C Mitogen-Activated Protein Kinase 3 biology Liver Neoplasms Imidazoles Cell cycle ErbB Receptors Endocrinology Liver Mechanics of Materials Ceramics and Composites Cancer research biology.protein Phosphorylation Signal Transduction |
| Zdroj: | Biomaterials. 35:7479-7487 |
| ISSN: | 0142-9612 |
| DOI: | 10.1016/j.biomaterials.2014.05.022 |
| Popis: | Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed lethal cancers in the world. We previously showed two imidazolium salts (IBN-1 and IBN-9) with a moderate efficacy for HCC. Here we report a more potent imidazolium compound IBN-65 (1-benzyl-2-phenyl-3-(4-isopropyl)-benzyl-imidazolium chloride) and the associated mechanisms of action in a mouse model of HCC. The IC50 of this compound in various liver cancer cell lines was around 5 μm. IBN-65 dose-dependently arrested cell cycle at G1 phase and was associated with the down-regulation of the cyclin-dependent kinase-4, -6, cyclin D1, and cyclin E. In addition, IBN-65 induced apoptosis by down-regulating Survivin, Bcl-2 and up-regulating Bax, leading to sequential activation of Caspase-3, Caspase-9 and the cleavage of poly(ADP-ribose) polymerase (PARP). Dysregulation of the epidermal growth factor receptor (EGFR) signaling network has been frequently reported in HCC. We found that IBN-65 displayed a profound inhibitory effect on the EGFR/Raf/MEK/ERK signaling at the phosphorylation level. In Huh7 or Hep3B cells, pretreatment with IBN-65 attenuated EGF-induced phosphorylation of both EGFR and the downstream p44/42 MAPK. A siRNA knockdown of EGFR also proved that IBN-65 induced apoptosis mostly through inhibiting downstream EGFR pathway signaling, much less at the receptor level. Infrequent administration of IBN-65 (i.p., 5 mg/kg once weekly for four weeks) to mice bearing the Huh7 cells significantly reduced the tumor volume by 65% without affecting the body weight. Critically, many of the anti-tumor signaling features observed in the HCC cell lines were recaptured in the xenografted tissues. Thus, the metal-free imidazolium compound IBN-65 could be a potential candidate towards therapeutic development for HCC. |
| Databáze: | OpenAIRE |
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