Suppression of β-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10.

Nan Li,Kevin Lee,Adam B Keeton,Sara Sigler,Andrzej Wierzbicki,Bing Zhu,Xi Chen,Bernard Gary,Wei Zhang,Verónica Ramírez-Alcántara,E Alan Salter,Joshua C Canzoneri,Yonghe Li,Gary A Piazza,Mary P Moyer

doi:10.18632/oncotarget.4741

Abstract

Previous studies suggest the anti-inflammatory drug, sulindac inhibits tumorigenesis by a COX independent mechanism involving cGMP PDE inhibition. Here we report that the cGMP PDE isozymes, PDE5 and 10, are elevated in colon tumor cells compared with normal colonocytes, and that inhibitors and siRNAs can selectively suppress colon tumor cell growth. Combined treatment with inhibitors or dual knockdown suppresses tumor cell growth to a greater extent than inhibition from either isozyme alone. A novel sulindac derivative, ADT-094 was designed to lack COX-1/-2 inhibitory activity but have improved potency to inhibit PDE5 and 10. ADT-094 displayed >500 fold higher potency to inhibit colon tumor cell growth compared with sulindac by activating cGMP/PKG signaling to suppress proliferation and induce apoptosis. Combined inhibition of PDE5 and 10 by treatment with ADT-094, PDE isozyme-selective inhibitors, or by siRNA knockdown also suppresses β-catenin, TCF transcriptional activity, and the levels of downstream targets, cyclin D1 and survivin. These results suggest that dual inhibition of PDE5 and 10 represents novel strategy for developing potent and selective anticancer drugs.

Highlights

Colorectal cancer (CRC) is the 3rd most common malignant disease in the Western world and is a major public health problem that accounts for up to 12% of all newly diagnosed cancers in the United States [1]
Despite the promising cancer chemopreventive activity of non-steroidal anti-inflammatory drugs (NSAIDs) as evident by epidemiological and preclinical studies, this class of drugs is not recommended for long-term use in humans due to the potential for toxicities associated with COX inhibition and the suppression of physiological prostaglandins
We have previously reported that cGMP PDE inhibition and activation of cGMP/protein kinase G (PKG) pathway is closely associated with the tumor cell growth inhibitory and apoptosis inducing activity of sulfide metabolite of sulindac (SS) [12, 14, 20, 33, 35]

Summary

Introduction

Colorectal cancer (CRC) is the 3rd most common malignant disease in the Western world and is a major public health problem that accounts for up to 12% of all newly diagnosed cancers in the United States [1]. Epidemiological studies have reported that the longterm use of non-steroidal anti-inflammatory drugs (NSAIDs) can significantly reduce the incidence and risk of death from colorectal cancer by as much as 50–60% [3]. Certain prescription-strength NSAIDs such as sulindac have been reported to cause regression of precancerous adenomas in individuals with familial adenomatous polyposis (FAP) [4]. These observations are consistent with studies in rodent models reporting that NSAIDs strongly inhibit intestinal tumorigenesis induced by chemical carcinogens or by mutations in the APC gene [5, 6]. The risk of gastrointestinal, renal, and cardiovascular toxicity associated with COX-1 or COX-2 inhibition and suppression of www.impactjournals.com/oncotarget physiological prostaglandins limits the long-term use of NSAIDs for chemoprevention [7]

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Results

Conclusion