Sigler Sara, Abdel-Halim Mohammad, Fathalla Reem K, Da Silva Luciana Madeira, Keeton Adam B, Maxuitenko Yulia Y, Berry Kristy L, Zhou Gang, Engel Matthias, Abadi Ashraf H, Piazza Gary A
Department of Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36608, USA.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
Anticancer Agents Med Chem. 2025;25(1):52-62. doi: 10.2174/0118715206318802240821114353.
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.
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 .
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.
Anticancer activity of RF26 was studied using human CRC cell lines. Effects on cell growth, cGMPdependent 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.
RF26 was appreciably more potent than celecoxib and sildenafil to suppress CRC cell growth and was effective at concentrations that 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.
Further evaluation of RF26 for the prevention or treatment of cancer and studying the role of PDE5 in tumorigenesis are warranted.
既往研究报道，环磷酸鸟苷特异性磷酸二酯酶5（cGMP-specific PDE5）同工酶在结肠腺瘤和腺癌中过表达，且对结肠癌细胞增殖至关重要，而据报道，PDE5选择性抑制剂（如西地那非）具有癌症化学预防活性。
本研究旨在使用结直肠癌（CRC）细胞确定新型PDE5抑制剂RF26的抗癌活性以及PDE5在CRC肿瘤生长中的作用。
本研究的目的是表征一种新型塞来昔布衍生物RF26在先前报道缺乏COX-2抑制作用但具有强效PDE5抑制活性的CRC细胞中的抗癌活性。
使用人CRC细胞系研究RF26的抗癌活性。测量其对细胞生长、环磷酸鸟苷依赖性蛋白激酶（PKG）活性、β-连环蛋白水平、TCF/LEF转录活性、细胞周期分布和凋亡的影响。使用CRISPR/cas9 PDE5基因敲除技术确定PDE5是否介导RF26的抗癌活性，并验证PDE5作为癌症靶点。
RF26在抑制CRC细胞生长方面明显比塞来昔布和西地那非更有效，并且在激活PKG信号传导的浓度下有效。RF26在相同浓度范围内抑制β-连环蛋白水平和TCF/LEF转录活性，并诱导G1期细胞周期停滞和凋亡。CRISPR/cas9 PDE5基因敲除的CRC细胞对RF26的敏感性降低，增殖比亲本细胞慢，并且在小鼠中未能形成肿瘤。
有必要进一步评估RF26在癌症预防或治疗中的作用，并研究PDE5在肿瘤发生中的作用。
