TY - JOUR
T1 - PDE5 and PDE10 inhibition activates cGMP/PKG signaling to block Wnt/β-catenin transcription, cancer cell growth, and tumor immunity
AU - Piazza, Gary A.
AU - Ward, Antonio
AU - Chen, Xi
AU - Maxuitenko, Yulia
AU - Coley, Alex
AU - Aboelella, Nada S.
AU - Buchsbaum, Donald J.
AU - Boyd, Michael R.
AU - Keeton, Adam B.
AU - Zhou, Gang
N1 - Funding Information:
This publication was supported, in part, by the National Cancer Institute of the National Institutes of Health under awards R01CA155638 , R01CA197147 , and R01CA131378 .
Publisher Copyright:
© 2020
PY - 2020/8
Y1 - 2020/8
N2 - Although numerous reports conclude that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer activity, this common drug class is not recommended for long-term use because of potentially fatal toxicities from cyclooxygenase (COX) inhibition. Studies suggest the mechanism responsible for the anticancer activity of the NSAID sulindac is unrelated to COX inhibition but instead involves an off-target, phosphodiesterase (PDE). Thus, it might be feasible develop safer and more efficacious drugs for cancer indications by targeting PDE5 and PDE10, which are overexpressed in various tumors and essential for cancer cell growth. In this review, we describe the rationale for using the sulindac scaffold to design-out COX inhibitory activity, while improving potency and selectivity to inhibit PDE5 and PDE10 that activate cGMP/PKG signaling to suppress Wnt/β-catenin transcription, cancer cell growth, and tumor immunity.
AB - Although numerous reports conclude that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer activity, this common drug class is not recommended for long-term use because of potentially fatal toxicities from cyclooxygenase (COX) inhibition. Studies suggest the mechanism responsible for the anticancer activity of the NSAID sulindac is unrelated to COX inhibition but instead involves an off-target, phosphodiesterase (PDE). Thus, it might be feasible develop safer and more efficacious drugs for cancer indications by targeting PDE5 and PDE10, which are overexpressed in various tumors and essential for cancer cell growth. In this review, we describe the rationale for using the sulindac scaffold to design-out COX inhibitory activity, while improving potency and selectivity to inhibit PDE5 and PDE10 that activate cGMP/PKG signaling to suppress Wnt/β-catenin transcription, cancer cell growth, and tumor immunity.
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U2 - 10.1016/j.drudis.2020.06.008
DO - 10.1016/j.drudis.2020.06.008
M3 - Review article
C2 - 32562844
AN - SCOPUS:85086771857
VL - 25
SP - 1521
EP - 1527
JO - Drug Discovery Today
JF - Drug Discovery Today
SN - 1359-6446
IS - 8
ER -