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Targeting notch signaling pathway in breast cancer stem cells through drug repurposing approach

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Abstract

Breast cancer is recognized globally as one of the leading causes of malignant morbidity. It is a heterogeneous disease that accounts for 30 percent of all women diagnosed with cancer. To bring an anti-cancer drug from the bench to the bedside is an expensive and time-consuming process. The drug repurposing approach targets new enemies (new diseases) with old weapons (known drugs). The present study identified an FDA-approved drug targeting the γ-secretase complex involved in the Notch signaling pathway in breast cancer stem cells (BCSCs). A literature survey and in-silico study identified Venetoclax as a γ-secretase inhibitor (GSI) from 1615 FDA-approved drug compounds. In-silico docking potential of Venetoclax was better than the standard γ-secretase inhibitor RO4929097. Also, the molecular dynamics simulations of 200 ns confirmed the stability of the Venetoclax-γ-secretase complex. These findings suggest that the use of Venetoclax represents a potential γ-secretase inhibitor in breast cancer stem cells. Eventually, the in vitro and clinical evaluation will be needed to confirm the potential chemopreventive and treatment effects of Venetoclax against breast cancer and breast cancer stem cells.

Graphical Abstract

Venetoclax appeared as the most promising drug of the 1615 FDA-approved drugs. Our in-silico findings suggest that Venetoclax may act as a γ-secretase inhibitor against the Notch signaling pathway in breast cancer stem cells.

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Acknowledgements

Part of the results presented here was developed with the help of CENAPAD-SP (Centro Nacional de Processamento de Alto Desempenho em São Paulo) grant UNICAMP/FINEP- MCT, CENAPAD-UFC (Centro Nacional de Processamento de Alto Desempenho, at Universidade Federal, do Ceará) and Digital Research Alliance of Canada (DRAC).

Funding

No funding was received for conducting this study.

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Authors and Affiliations

  1. School of Biotechnology, Gautam Buddha University, Greater Noida, 201310, India

    Yamini Pathak, Amaresh Mishra & Vishwas Tripathi

  2. Laboratório de Modelagem Computacional - LaModel, Instituto de Ciências Exatas – ICEx, Universidade Federal de Alfenas - UNIFAL-MG, Alfenas, Minas Gerais, Brazil

    Ihosvany Camps

  3. High Performance & Quantum Computing Labs, Waterloo, Canada

    Ihosvany Camps

Authors
  1. Yamini Pathak
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  2. Ihosvany Camps
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  3. Amaresh Mishra
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  4. Vishwas Tripathi
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Contributions

YP and IC carried out the experiment. YP wrote the manuscript with support from VT, IC, and AM. VT helped supervise the project and finally approved the version to be submitted. All authors provided critical feedback and helped shape the research, analysis, and manuscript.

Corresponding author

Correspondence to Vishwas Tripathi.

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Pathak, Y., Camps, I., Mishra, A. et al. Targeting notch signaling pathway in breast cancer stem cells through drug repurposing approach. Mol Divers 27, 2431–2440 (2023). https://doi.org/10.1007/s11030-022-10561-y

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  • DOI: https://doi.org/10.1007/s11030-022-10561-y

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