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IJPER · Lens · Drug Repurposing Revealed Abemaciclib and Palbociclib as Inhibitor of Phosphodiesterase-5 (PDE5) in Cancer-Associated Fibroblasts Paving the Way for the Treatment of Breast Cancer

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Article · Volume 59, Issue 3 · pp. 1221–1230

Drug Repurposing Revealed Abemaciclib and Palbociclib as Inhibitor of Phosphodiesterase-5 (PDE5) in Cancer-Associated Fibroblasts Paving the Way for the Treatment of Breast Cancer

Norah Saeed Al-Zahrani1, Ayyub Ali Patel1, Basiouny El-Gamal1,2, Mohamed Abd Ellatif1,3, Khalid Ali Nasif1, Mohamed Babiker Abd Elrouf1, Heitham Mutwakil Mohammed4, Safaa Omer1, Marwa Saeed1, Muniera Mohieldeen1, Hagar Mohamed Mohamed5,6, Mohammad Rehan Ajmal7

  1. 1Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, SAUDI ARABIA.
  2. 2Healthcare and Pharma Department, Planaletix, Dubai, UNITED ARAB EMIRATES.
  3. 3Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, EGYPT.
  4. 4Department of Anatomy, College of Medicine, King Khalid University, Abha, SAUDI ARABIA.
  5. 5Department of Medical Laboratory Analysis, Faculty of Medical and Health Sciences, Liwa College, Abu Dhabi, UNITED ARAB EMIRATES.
  6. 6Department of Applied Medical Chemistry, Medical Research Institute, Alexandria University, Alexandria, EGYPT.
  7. 7Department of Biochemistry, Physical Biochemistry Research Laboratory, Faculty of Science, University of Tabuk, Tabuk, SAUDI ARABIA.

Abstract

Background: A common element of the tumor microenvironment, cancer-associated fibroblasts play a major role in the development of breast cancer via a variety of pathways. Studies show that cancer-associated fibroblasts over express phosphodiesterase-5 in comparison to normal fibroblasts and that this overexpression is linked to increased fibroblast activation and a more aggressive CAF phenotype. High PDE5 levels in CAFs contribute to the remodeling of the extracellular matrix, increased secretion of pro-tumorigenic factors and suppression of anti-tumor immune responses.Materials and Methods: Targeting PDE5 in CAFs thus offers a convincing method to interfere with these cells' pro-tumorigenic activities. The potential to inhibit PDE5 was examined for four FDA-approved CDK4/6 inhibitors: Abemaciclib, Palbociclib, Alvocidib and Ribociclib.Results: These drugs, with established safety profiles, were screened and docked against PDE5, showing binding affinities of -7.8, -7.8, -7.1 and -6.8 kcal/mol, respectively, compared to Sildenafil's -7.0 kcal/mol, a known inhibitor of PDE5. ADMET predictions, PASS analysis and Swiss Target Prediction affirmed their drug-like properties and potential for PDE5 inhibition.Conclusion: Based on these results, Abemaciclib and Palbociclib were chosen for in vitro experiments with cancer-associated fibroblasts. The 2 drugs significantly decreased the expression of PDE5 mRNA, indicating their potential as therapeutic agents for the treatment of breast cancer.

Keywords: Breast cancer; Cancer-associated fibroblasts; CDK4/6 inhibitors; Inhibitor; Phosphodiesterase-5 (PDE5)

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