Therapeutic effect of a multi-targeted imidazolium compound in hepatocellular carcinoma

Therapeutic effect of a multi-targeted imidazolium compound in hepatocellular carcinoma
Title:
Therapeutic effect of a multi-targeted imidazolium compound in hepatocellular carcinoma
Other Titles:
Biomaterials
Keywords:
Publication Date:
06 June 2014
Citation:
Began Gopalan, Karthikeyan Narayanan, Zhiyuan Ke, Ting Lu, Yugen Zhang, Lang Zhuo, Therapeutic effect of a multi-targeted imidazolium compound in hepatocellular carcinoma, Biomaterials, Volume 35, Issue 26, 2014, Pages 7479-7487, ISSN 0142-9612, https://doi.org/10.1016/j.biomaterials.2014.05.022.
Abstract:
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.
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PublisherCopyrights
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Description:
ISSN:
0142-9612
1878-5905
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