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Published on: February 6, 2015
Evaluation of the Anticancer Potential of Nitro-Benzimidazole Derivatives in Breast Cancer
Ayşe Büşranur Celik1,2, Kezban Ucar Cifci3, Merve Akdag1
1Division of Medical Biochemistry, Department of Basic Medical Sciences, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Türkiye.
Introduction/Objective:
Breast cancer is the most common malignancy among women worldwide, and the emergence of resistance to anthracycline-based chemotherapy remains a major clinical challenge. Benzimidazole scaffolds have attracted considerable interest in medicinal chemistry due to their broad pharmacological properties and anticancer potential. This study aimed to investigate the anticancer activity, selectivity, and molecular mechanisms of novel nitro-benzimidazole derivatives in luminal and Adriamycin-resistant breast cancer cell lines.
Methods:
A series of benzimidazole derivatives was synthesized and evaluated using in silico pharmacokinetic analyses. Cytotoxicity was assessed by MTT assay in MCF-7, adriamycinresistant MCF-7 (MCF-7/Adr), and normal human fibroblast cells CCD-1072sk. The most active compound was further investigated by RT-qPCR-based gene expression and pathway enrichment analyses, flow cytometry-based evaluation of apoptosis and cell cycle distribution, fluorescence-based morphological analyses, and gene-metabolite interaction analysis.
Results:
Among the tested compounds, SN-1 exhibited the strongest antiproliferative activity, with IC₂⁽ values of 4.86 ± 0.27 μM in MCF-7 cells and 8.62 ± 1.51 μM in MCF-7/Adr cells, along with a high selectivity index. SN-1 significantly induced apoptosis and caused cell cycle arrest at the G2/M phase in MCF-7 cells and at the G0/G1 phase in MCF-7/Adr cells. Gene enrichment and metabolite interaction analyses revealed modulation of apoptosis-, cell cycle-, and metabolism-related pathways, including associations with glycerol, ATP, and ADP.
Discussion:
These findings suggest that SN-1 exerts selective anticancer activity against both drug-sensitive and chemoresistant breast cancer cells through the regulation of apoptosis, cell cycle progression, and metabolic pathways. The observed effects on resistant cells further indicate the therapeutic potential of SN-1 in overcoming chemotherapy resistance.
Conclusion:
The nitro-benzimidazole derivative SN-1 exhibits strong and selective anticancer effects in both drug-sensitive and chemoresistant breast cancer cells by modulating apoptosis, cell cycle progression, and key metabolic pathways.
Insights
A novel nitro-benzimidazole derivative, SN-1, shows potent anticancer activity against both sensitive and Adriamycin-resistant breast cancer cells. SN-1 effectively targets apoptosis, cell cycle, and metabolism, offering potential to overcome chemotherapy resistance.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Molecular Biology
Background:
- Breast cancer is a leading cause of mortality in women globally.
- Chemotherapy resistance, particularly to anthracyclines, presents a significant clinical hurdle.
- Benzimidazole derivatives are recognized for their diverse pharmacological activities, including anticancer potential.
Purpose of the Study:
- To synthesize and evaluate novel nitro-benzimidazole derivatives for anticancer activity.
- To assess the selectivity of these compounds against breast cancer cell lines, including Adriamycin-resistant ones.
- To elucidate the molecular mechanisms underlying the anticancer effects of the most potent derivative.
Main Methods:
- Synthesis of benzimidazole derivatives and in silico pharmacokinetic analysis.
- Cytotoxicity assessment using MTT assays in MCF-7, MCF-7/Adr, and CCD-1072sk cells.
- Detailed mechanistic studies including gene expression, apoptosis, cell cycle analysis, and metabolite interaction profiling.
Main Results:
- The compound SN-1 demonstrated significant antiproliferative effects with high selectivity.
- SN-1 induced apoptosis and cell cycle arrest at distinct phases (G2/M or G0/G1) in different cell lines.
- Pathway analysis revealed modulation of apoptosis, cell cycle, and metabolism-related pathways, with links to glycerol, ATP, and ADP.
Conclusions:
- SN-1 exhibits potent and selective anticancer activity against both drug-sensitive and chemoresistant breast cancer cells.
- The compound functions by regulating apoptosis, cell cycle progression, and metabolic pathways.
- SN-1 holds promise as a therapeutic agent to overcome chemotherapy resistance in breast cancer.
