Repurposing risperidone as an anti-angiogenic agent for triple-negative breast cancer: a computational to in ovo
Anisha Jain1, Anil Kumar Belagal Motatis2,3, Chandan Dharmashekar4
1Department of Biotechnology, JSS Science and Technology University, Mysuru, Karnataka, India.
Introduction:
Triple-negative breast cancer (TNBC) is a challenging subtype of breast cancer to treat because it lacks the expression of progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2). A significant majority of deaths related to cancer are caused by tumor metastasis and angiogenesis. Vascular endothelial growth factor receptor 2 (VEGFR2) plays a significant role in angiogenesis. Instead of developing new molecules, drug repurposing, also known as repositioning, seeks innovative uses for outdated drugs or those that fail due to ineffectiveness.
Methods:
In this study, we performed high-throughput virtual screening of FDA approved drug library taken from Enamine bioactive collection targeting VEGFR proteins, and the top hit compounds analyzed by molecular dynamics simulations and MM-GBSA were considered for further in vitro analyses against human breast cancer cells, MDA-MB-231 and MDA-MB-468 cells followed by in ovo assay using the Chorioallantoic Membrane (CAM) model.
Results:
The results revealed that risperidone was effective against triple-negative breast cancer, with IC50 values ranging from 46.53 to 49.76 µM. The findings of our study demonstrated that risperidone, an antipsychotic drug, could successfully inhibit human breast cancer cells in silico, in vitro and in ovo.
Discussion:
We could prove that a structure-based drug repurposing approach is an effective strategy to produce a promising antiangiogenic repurposed drug that could also inhibit VEGFR2 in breast cancer. Although risperidone showed modest potency, its clinical availability and repurposing potential support further evaluation in preclinical and clinical settings.
Insights
Repurposing the antipsychotic drug risperidone shows promise for treating triple-negative breast cancer by inhibiting vascular endothelial growth factor receptor 2 (VEGFR2). This drug repurposing strategy offers a potential new avenue for TNBC therapy.
Area of Science:
- Oncology
- Pharmacology
- Drug Discovery
Background:
- Triple-negative breast cancer (TNBC) lacks ER, PR, and HER2 expression, making it difficult to treat.
- Tumor metastasis and angiogenesis, driven by factors like VEGFR2, are major causes of cancer mortality.
- Drug repurposing offers a strategy to find new uses for existing medications.
Purpose of the Study:
- To identify potential drug candidates for TNBC through high-throughput virtual screening.
- To evaluate the efficacy of repurposed drugs targeting VEGFR2 in TNBC models.
- To investigate the anti-angiogenic and anti-cancer properties of identified compounds.
Main Methods:
- High-throughput virtual screening of FDA-approved drugs targeting VEGFR proteins.
- Molecular dynamics simulations and MM-GBSA analysis.
- In vitro assays using MDA-MB-231 and MDA-MB-468 cells, and in ovo CAM assay.
Main Results:
- Risperidone demonstrated efficacy against TNBC cell lines with IC50 values between 46.53 and 49.76 µM.
- The antipsychotic drug risperidone showed inhibitory effects on human breast cancer cells in silico, in vitro, and in ovo.
- The study confirmed risperidone's effectiveness in inhibiting VEGFR2 in breast cancer models.
Conclusions:
- Structure-based drug repurposing is effective for identifying anti-angiogenic drugs targeting VEGFR2 in breast cancer.
- Risperidone, despite modest potency, shows potential for TNBC treatment due to its clinical availability.
- Further preclinical and clinical evaluations of risperidone for TNBC are warranted.
