Abstract
BackgroundMicrotubule Targeting Agents (MTAs) including paclitaxel, colchicine and vinca alkaloids are widely used in the treatment of various cancers. As with most chemotherapeutic agents, adverse effects and drug resistance are commonly associated with the clinical use of these agents. Methyl 2-(5-fluoro-2-hydroxyphenyl)-1H- benzo[d]imidazole-5-carboxylate (MBIC), a benzimidazole derivative displays greater toxicity against various cancer compared to normal human cell lines. The present study, focused on the cytotoxic effects of MBIC against HeLa cervical cancer cells and possible actions on the microtubule assembly.MethodsApoptosis detection and cell-cycle assays were performed to determine the type of cell death and the phase of cell cycle arrest in HeLa cells. Tubulin polymerization assay and live-cell imaging were performed to visualize effects on the microtubule assembly in the presence of MBIC. Mitotic kinases and mitochondrial-dependent apoptotic proteins were evaluated by Western blot analysis. In addition, the synergistic effect of MBIC with low doses of selected chemotherapeutic actions were examined against the cancer cells.ResultsResults from the present study showed that following treatment with MBIC, the HeLa cells went into mitotic arrest comprising of multi-nucleation and unsegregated chromosomes with a prolonged G2-M phase. In addition, the HeLa cells showed signs of mitochondrial-dependant apoptotic features such as the release of cytochrome c and activation of caspases. MBIC markedly interferes with tubulin polymerization. Western blotting results indicated that MBIC affects mitotic regulatory machinery by up-regulating BubR1, Cyclin B1, CDK1 and down-regulation of Aurora B. In addition, MBIC displayed synergistic effect when given in combination with colchicine, nocodazole, paclitaxel and doxorubicin.ConclusionTaken together, our study demonstrated the distinctive microtubule destabilizing effects of MBIC against cervical cancer cells in vitro. Besides that, MBIC exhibited synergistic effects with low doses of selected anticancer drugs and thus, may potentially reduce the toxicity and drug resistance to these agents.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0332-0) contains supplementary material, which is available to authorized users.
Highlights
Microtubule Targeting Agents (MTAs) including paclitaxel, colchicine and vinca alkaloids are widely used in the treatment of various cancers
Methyl 2-(5-fluoro-2-hydroxyphenyl)-1Hbenzo[d]imidazole-5-carboxylate (MBIC) is cytotoxic against different human cancer cell lines MTT assays were performed to evaluate the inhibitory activity of MBIC on HCT-116, A549, HepG-2, Human cervical cancer (HeLa) cancer cell lines compared to human embryonic normal liver cell line (WRL-68)
We found that the half maximal inhibitory concentration (IC50) of MBIC on human cancer cell lines was
Summary
Microtubule Targeting Agents (MTAs) including paclitaxel, colchicine and vinca alkaloids are widely used in the treatment of various cancers. The present study, focused on the cytotoxic effects of MBIC against HeLa cervical cancer cells and possible actions on the microtubule assembly. Cervical cancer is the third most common cancer and the fourth cause of death in women worldwide. More than 85 % of deaths due to cervical cancer occur mostly in developing countries. South-central Asia is reported to have among the highest incidences of cervical cancer [1]. In Malaysia, cervical cancer is rated as second most common cancer among women [2]. Human papillomavirus (HPV) infection is the main cause of cervical cancer [3]. It is well documented that cervical cancer cannot develop in the absence of the persistent HPV DNA [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
