TY - JOUR
T1 - Suppression of colon tumorigenesis in mutant apc mice by a novel PDE10 inhibitor that reduces oncogenic β-catenin
AU - Lee, Kevin J.
AU - Chang, Wen Chi L.
AU - Chen, Xi
AU - Valiyaveettil, Jacob
AU - Ramirez-Alcantara, Veronica
AU - Gavin, Elaine
AU - Musiyenko, Alla
AU - Da Silva, Luciana Madeira
AU - Annamdevula, Naga S.
AU - Leavesley, Silas J.
AU - Ward, Antonio
AU - Mattox, Tyler
AU - Lindsey, Ashley S.
AU - Andrews, Joel
AU - Zhu, Bing
AU - Wood, Charles
AU - Neese, Ashleigh
AU - Nguyen, Ashley
AU - Berry, Kristy
AU - Maxuitenko, Yulia
AU - Moyer, Mary Pat
AU - Nurmemmedov, Elmar
AU - Gorman, Greg
AU - Coward, Lori
AU - Zhou, Gang
AU - Keeton, Adam B.
AU - Cooper, Harry S.
AU - Clapper, Margie L.
AU - Piazza, Gary A.
N1 - Funding Information:
Funding provided by the NCI, NIH under Award Numbers 1R01CA131378, 1RO1CA148817, 1RO1CA197147, and 1RO1CA155638, to G.A. Piazza and P30 CA006927, to Fox Chase Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Funding Information:
The animal work was performed with the technical support of the following core facilities at Fox Chase Cancer Center: Laboratory Animal Facility, Genotyping Components of the Genomics Facility, Small Animal Imaging Component of the Biological Imaging Facility, and the Biostatistics and Bioinformatics Facility. Funding provided by the NCI, NIH under Award Numbers 1R01CA131378, 1RO1CA148817, 1RO1CA197147, and 1RO1CA155638, to G.A. Piazza and P30 CA006927, to Fox Chase Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/11
Y1 - 2021/11
N2 - Previous studies have reported that phosphodiesterase 10A (PDE10) is overexpressed in colon epithelium during early stages of colon tumorigenesis and essential for colon cancer cell growth. Here we describe a novel non-COX inhibitory derivative of the anti-inflammatory drug, sulindac, with selective PDE10 inhibitory activity, ADT 061. ADT 061 potently inhibited the growth of colon cancer cells expressing high levels of PDE10, but not normal colonocytes that do not express PDE10. The concentration range by which ADT 061 inhibited colon cancer cell growth was identical to concentrations that inhibit recombinant PDE10. ADT 061 inhibited PDE10 by a competitive mechanism and did not affect the activity of other PDE isozymes at concentrations that inhibit colon cancer cell growth. Treatment of colon cancer cells with ADT 061 activated cGMP/PKG signaling, induced phosphorylation of oncogenic β-catenin, inhibited Wnt-induced nuclear translocation of β-catenin, and suppressed TCF/LEF transcription at concentrations that inhibit cancer cell growth. Oral administration of ADT 061 resulted in high concentrations in the colon mucosa and significantly suppressed the formation of colon adenomas in the Apc+/min-FCCC mouse model of colorectal cancer without discernable toxicity. These results support the development of ADT 061 for the treatment or prevention of adenomas in individuals at risk of developing colorectal cancer.
AB - Previous studies have reported that phosphodiesterase 10A (PDE10) is overexpressed in colon epithelium during early stages of colon tumorigenesis and essential for colon cancer cell growth. Here we describe a novel non-COX inhibitory derivative of the anti-inflammatory drug, sulindac, with selective PDE10 inhibitory activity, ADT 061. ADT 061 potently inhibited the growth of colon cancer cells expressing high levels of PDE10, but not normal colonocytes that do not express PDE10. The concentration range by which ADT 061 inhibited colon cancer cell growth was identical to concentrations that inhibit recombinant PDE10. ADT 061 inhibited PDE10 by a competitive mechanism and did not affect the activity of other PDE isozymes at concentrations that inhibit colon cancer cell growth. Treatment of colon cancer cells with ADT 061 activated cGMP/PKG signaling, induced phosphorylation of oncogenic β-catenin, inhibited Wnt-induced nuclear translocation of β-catenin, and suppressed TCF/LEF transcription at concentrations that inhibit cancer cell growth. Oral administration of ADT 061 resulted in high concentrations in the colon mucosa and significantly suppressed the formation of colon adenomas in the Apc+/min-FCCC mouse model of colorectal cancer without discernable toxicity. These results support the development of ADT 061 for the treatment or prevention of adenomas in individuals at risk of developing colorectal cancer.
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U2 - 10.1158/1940-6207.CAPR-21-0208
DO - 10.1158/1940-6207.CAPR-21-0208
M3 - Article
C2 - 34584001
AN - SCOPUS:85119924904
VL - 14
SP - 995
EP - 1008
JO - Cancer Prevention Research
JF - Cancer Prevention Research
SN - 1940-6207
IS - 11
ER -