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Published on: February 6, 2015
Vitamin D analog calcitriol for breast cancer therapy; an integrated drug discovery approach
Nagaraj B S1, Krishnan Namboori P K2, Krishna Swaroop Akey1
1Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamilnadu, India.
Abstract:
As breast cancer remains leading cause of cancer death globally, it is essential to develop an affordable breast cancer therapy in underdeveloped countries. Drug repurposing offers potential to address gaps in breast cancer treatment. Molecular networking studies were performed for drug repurposing approach by using heterogeneous data. The PPI networks were built to select the target genes from the EGFR overexpression signaling pathway and its associated family members. The selected genes EGFR, ErbB2, ErbB4 and ErbB3 were allowed to interact with 2637 drugs, leads to PDI network construction of 78, 61, 15 and 19 drugs, respectively. As drugs approved for treating non cancer-related diseases or disorders are clinically safe, effective, and affordable, these drugs were given considerable attention. Calcitriol had shown significant binding affinities with all four receptors than standard neratinib. The RMSD, RMSF, and H-bond analysis of protein-ligand complexes from molecular dynamics simulation (100 ns), confirmed the stable binding of calcitriol with ErbB2 and EGFR receptors. In addition, MMGBSA and MMP BSA also affirmed the docking results. These in-silico results were validated with in-vitro cytotoxicity studies in SK-BR-3 and Vero cells. The IC50 value of calcitriol (43.07 mg/ml) was found to be lower than neratinib (61.50 mg/ml) in SK-BR-3 cells. In Vero cells the IC50 value of calcitriol (431.05 mg/ml) was higher than neratinib (404.95 mg/ml). It demonstrates that calcitriol suggestively downregulated the SK-BR-3 cell viability in a dose-dependent manner. These implications revealed calcitriol has shown better cytotoxicity and decreased the proliferation rate of breast cancer cells than neratinib.Communicated by Ramaswamy H. Sarma.
Insights
This study repurposed calcitriol as a potential breast cancer therapy. Calcitriol demonstrated superior binding affinity and cytotoxicity against cancer cells compared to neratinib in silico and in vitro.
Area of Science:
- Oncology
- Pharmacology
- Computational Biology
Background:
- Breast cancer is a leading global cause of cancer mortality, necessitating affordable therapies, especially for underdeveloped nations.
- Drug repurposing presents a viable strategy to identify safe, effective, and economical breast cancer treatments.
- Targeting the Epidermal Growth Factor Receptor (EGFR) pathway is crucial for breast cancer therapy development.
Purpose of the Study:
- To identify existing drugs that can be repurposed for breast cancer treatment through molecular networking and computational analysis.
- To evaluate the efficacy of calcitriol, a vitamin D analog, as a potential breast cancer therapeutic agent by targeting EGFR family receptors.
- To compare the therapeutic potential of calcitriol against neratinib, a standard breast cancer drug.
Main Methods:
- Constructed protein-protein interaction (PPI) networks to identify key target genes (EGFR, ErbB2, ErbB4, ErbB3) in the EGFR signaling pathway.
- Built a drug-target interaction (PDI) network by analyzing interactions between 2637 drugs and the selected target genes.
- Employed molecular dynamics simulations, docking studies (MMGBSA, MMPBSA), and in vitro cytotoxicity assays (IC50) for validation.
Main Results:
- Calcitriol exhibited stronger binding affinities to EGFR, ErbB2, ErbB4, and ErbB3 than neratinib.
- Molecular dynamics simulations confirmed stable binding of calcitriol with ErbB2 and EGFR receptors.
- In vitro studies showed calcitriol significantly reduced SK-BR-3 breast cancer cell viability with a lower IC50 value than neratinib.
Conclusions:
- Calcitriol demonstrates significant potential as an affordable and effective repurposed drug for breast cancer therapy.
- Calcitriol exhibits superior cytotoxicity and antiproliferative effects on breast cancer cells compared to neratinib.
- Further clinical investigation of calcitriol is warranted for breast cancer treatment, particularly in resource-limited settings.
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