Novel Celecoxib Derivative, RF26, Blocks Colon Cancer Cell Growth by Inhibiting PDE5, Activating cGMP/PKG Signaling, and Suppressing β-catenin-dependent Transcription


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Abstract

Background:Previous studies have reported that the cGMP-specific PDE5 isozyme is overexpressed in colon adenomas and adenocarcinomas and essential for colon cancer cell proliferation, while PDE5 selective inhibitors (e.g., sildenafil) have been reported to have cancer chemopreventive activity.

Aim:This study aimed to determine the anticancer activity of a novel PDE5 inhibitor, RF26, using colorectal cancer (CRC) cells and the role of PDE5 in CRC tumor growth in vivo.

Objective:The objective of this study was to characterize the anticancer activity of a novel celecoxib derivative, RF26, in CRC cells previously reported to lack COX-2 inhibition but have potent PDE5 inhibitory activity.

Methods:Anticancer activity of RF26 was studied using human CRC cell lines. Its effects on intracellular cGMP levels, cGMP-dependent protein kinase (PKG) activity, β-catenin levels, TCF/LEF transcriptional activity, cell cycle distribution, and apoptosis were measured. CRISPR/cas9 PDE5 knockout techniques were used to determine if PDE5 mediates the anticancer activity of RF26 and validate PDE5 as a cancer target.

Results:RF26 was appreciably more potent than celecoxib and sildenafil to suppress CRC cell growth and was effective at concentrations that increased intracellular cGMP levels and activated PKG signaling. RF26 suppressed β-catenin levels and TCF/LEF transcriptional activity and induced G1 cell cycle arrest and apoptosis within the same concentration range. CRISPR/cas9 PDE5 knockout CRC cells displayed reduced sensitivity to RF26, proliferated slower than parental cells, and failed to establish tumors in mice.

Conclusion:Further evaluation of RF26 for the prevention or treatment of cancer and studying the role of PDE5 in tumorigenesis are warranted.

About the authors

Sara Sigler

Department of Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama

Email: info@benthamscience.net

Mohammad Abdel-Halim

Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo

Author for correspondence.
Email: info@benthamscience.net

Reem Fathalla

Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo

Email: info@benthamscience.net

Luciana Da Silva

Department of Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama

Email: info@benthamscience.net

Adam Keeton

Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University

Email: info@benthamscience.net

Yulia Maxuitenko

Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University

Email: info@benthamscience.net

Kristy Berry

Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University

Email: info@benthamscience.net

Gang Zhou

Georgia Cancer Center, Department of Medicine, Medical College of Georgia, Augusta University

Email: info@benthamscience.net

Matthias Engel

Pharmaceutical and Medicinal Chemistry, Saarland University

Email: info@benthamscience.net

Ashraf Abadi

Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo

Email: info@benthamscience.net

Gary Piazza

Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University

Author for correspondence.
Email: info@benthamscience.net

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