Mechanisms of the anti-tumor activity of Methyl 2-(-5-fluoro-2-hydroxyphenyl)-1 H-benzo[d]imidazole-5-carboxylate against breast cancer in vitro and in vivo
Metrics: PDF 1117 views | HTML 1961 views | ?
Mohadeseh Hasanpourghadi1, Ashok Kumar Pandurangan1, Chandrabose Karthikeyan2, Piyush Trivedi2, Mohd Rais Mustafa1
1Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia
2School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, 462033, India
Mohd Rais Mustafa, email: email@example.com
Keywords: breast cancer, microtubule targeting agent, mitotic arrest, mitotic slippage, drug resistance
Received: October 19, 2016 Accepted: March 06, 2017 Published: March 16, 2017
Microtubule Targeting Agents (MTAs) induce cell death through mitotic arrest, preferentially affecting rapidly dividing cancer cells over slowly proliferating normal cells. Previously, we showed that Methyl 2-(-5-fluoro-2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (MBIC) acts as a potential MTA. In this study, we demonstrated that MBIC exhibits greater toxicity towards non-aggressive breast cancer cell-line, MCF-7 (IC50 = 0.73 ± 0.0 μM) compared to normal fibroblast cell-line, L-cells (IC50 = 59.6 ± 2.5 μM). The IC50 of MBIC against the aggressive breast cancer cell-line, MDA-MB-231 was 20.4 ± 0.2 μM. We hypothesized that the relatively high resistance of MDA-MB-231 cells to MBIC is associated with p53 mutation. We investigated p53 and three of its downstream proteins: survivin, cyclin dependent kinase (Cdk1) and cyclin B1. Following treatment with MBIC, survivin co-immunoprecipitated with caspases with higher affinity in MDA-MB-231 compared to MCF-7 cells. Furthermore, silencing survivin caused a 4.5-fold increase in sensitivity of MDA-MB-231 cells to MBIC (IC50 = 4.4 ± 0.3). In addition, 4 weeks of MBIC administration in MDA-MB-231 cells inoculated BALB/c nude mice resulted in 79.7% reduction of tumor volume compared to the untreated group with no severe sign of toxicity. Our results demonstrated MBIC has multiple anti-tumor actions and could be a potential drug in breast cancer therapy.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.