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In Silico Study of a Small Bioactive Molecule Targeting Topoisomerase II and P53-MDM2 Complex in Triple-Negative
Vishal Singh1, Suman Verma2, Fiza Fatima3
1Department of Applied Sciences, Indian Institute of Information Technology Allahabad, Allahabad 211015, Uttar Pradesh,India.
Abstract:
Treatment of triple-negative breast cancer (TNBC) is very challenging as only few therapeutic options are available, including chemotherapy. Thus, a constant search for new and effective approaches of therapy that could potentially fight against TNBC and mitigate side effects is "turn-on". Recently, multitarget therapy has come up with huge possibilities, and it may possibly be useful to overcome several concurrent challenges in cancer therapy. Herein, we proposed the inhibition of both Topoisomerase II enzyme and p53-MDM2 (p53 cavity in MDM2) protein complex by the same bioactive molecules for multitarget therapy. RNA-seq analysis was performed to get a network of essential proteins involved in the apoptosis pathway by considering the triple-negative breast cancer cell line (MDA-MB-231). All of the untreated duplicate sample data were retrieved from NCBI (GSC149768). Further, via in silico screening, potent bioactive molecules were screened out to target both Topo II and the p53-MDM2 complex. The results of ligand-based screening involving docking, MMGBSA, ADME/T, MD simulation, and PCA suggested that resveratrol, a plant bioactive molecule, showed more potential binding in the same cavity of target proteins compared with doxorubicin for Topo IIα (5GWK) and etoposide for the second protein target (p53-MDM2 complex; 4OQ3) as the control drug. This is also evident from the in vitro validation in case of triple-negative breast cancer cell lines (MDA-MB-231) and Western blotting analysis. Thus, it paves the scope of multitargeting against triple-negative breast cancer.
Insights
Multitarget therapy using resveratrol shows promise for treating triple-negative breast cancer (TNBC). This approach inhibits Topoisomerase II and the p53-MDM2 complex, offering a new strategy against this challenging cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to limited treatment options.
- Chemotherapy remains a primary treatment, but novel approaches are crucial to improve efficacy and reduce side effects.
- Multitarget therapy offers a promising strategy to address complex cancer mechanisms and overcome resistance.
Purpose of the Study:
- To investigate the potential of inhibiting both Topoisomerase II and the p53-MDM2 protein complex simultaneously using single bioactive molecules for TNBC treatment.
- To identify novel therapeutic agents capable of multitargeting key pathways in TNBC.
Main Methods:
- RNA-sequencing analysis of MDA-MB-231 cells to identify essential proteins in apoptosis pathways.
- In silico screening, including docking, MMGBSA, ADME/T, MD simulations, and PCA, to identify potent bioactive molecules.
- In vitro validation using TNBC cell lines (MDA-MB-231) and Western blotting analysis.
Main Results:
- Resveratrol, a plant-derived bioactive molecule, was identified as a potent inhibitor targeting both Topoisomerase IIα and the p53-MDM2 complex.
- In silico analyses indicated resveratrol's strong binding affinity to both targets, comparable or superior to control drugs like doxorubicin and etoposide.
- In vitro experiments confirmed resveratrol's efficacy in TNBC cell lines and Western blotting analysis supported its mechanism of action.
Conclusions:
- Resveratrol demonstrates significant potential as a multitargeting therapeutic agent for triple-negative breast cancer.
- This study provides a strong foundation for developing novel, effective therapies against TNBC by targeting multiple pathways simultaneously.
- The findings open new avenues for cancer treatment strategies focusing on multitargeting approaches.
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