cover
Article Menu

Journal Browser
Vol. 3 (2024)
Vol. 2 (2023)
Vol. 1 (2022)
Journal Insights

Frequency: Quarterly                  

Time to first decision: 2.4 Weeks

Submission to publication: 4 Weeks        

Acceptance rate: 26%

ISSN: 2972-3388

Announcement more >>
13 November 2023 Congratulations! World’s Top 2% Scientists 2023 of Cancer Insight
13 November 2023 Invitation to Submit Papers to Cancer Insight (CI)
15 December 2022 Call for Editorial Board Members for CI
Recommend Papers
article figure E3 ubiquitin ligase-dependent regulatory mechanism of TRIM family in carcinogenesis
article figure Mechanism of congenital lymphocytes and intestinal immunity regulated by gut microbial metabolites via metabolite-sensing receptor Ffar2
article figure Role of Natural Products in Combating Cancer
article figure How Does Lncrna Regulation Impact Cancer Metastasis
Open Access Review

Novel sulindac derivatives for colorectal cancer chemoprevention that target cGMP phosphodiesterases to suppress Wnt/β-catenin transcriptional activity

by Sindhu Ramesh a ,  Peyton Johnson a ,  Khalda Fadlalla a ,  Austin Moore a ,  Chung-Hui Huang a ,  Kristy Berry a ,  Yulia Y Maxuitenko a ,  Xi Chen a ,  Adam B Keeton a ,  Gang Zhou b  and  Gary Piazza a,* orcid
a
Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA
b
Georgia Cancer Center, Augusta University, Augusta, GA, USA
*
Author to whom correspondence should be addressed.
CI  2023 3(1):28; https://doi.org/10.58567/ci03010003
Received: 21 September 2023 / Accepted: 20 November 2023 / Published Online: 30 November 2023
View Full-Text
Download PDF

Abstract

Approximately 28 million individuals in the United States face the risk of developing precancerous colonic adenomas (polyps) and potentially progressing to colorectal cancer (CRC). While a promising strategy for CRC prevention involves pharmacological intervention, such as cancer chemoprevention or interception, currently, there are no FDA-approved drugs capable of preventing the formation or progression of adenomas to adenocarcinoma. Numerous clinical, epidemiological, and preclinical studies have offered compelling evidence supporting the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in CRC chemoprevention. However, the prolonged use of NSAIDs is not FDA-approved due to potential life-threatening toxicities resulting from cyclooxygenase (COX) inhibition and the depletion of physiological prostaglandins. Despite indications that the COX inhibitory activity of NSAIDs may not be essential for their antineoplastic effects, the absence of a well-defined target impeded the development of derivatives that do not inhibit COX. Earlier research suggests that the inhibition of cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) may be responsible, at least in part, for the antineoplastic activity of the NSAID sulindac. This could potentially offer a novel target for CRC chemoprevention. To identify the cGMP PDE isozyme(s) contributing to the antineoplastic activity of sulindac, we synthesized a chemically diverse library of over 1500 compounds, all sharing the indene scaffold of sulindac. Subsequently, we screened these compounds for their impact on cancer cell growth and PDE inhibitory activity. From this screening, a series of lead compounds emerged. These compounds lacked COX-1 and COX-2 inhibitory activity, surpassing sulindac in potency to inhibit CRC cell growth. Importantly, they demonstrated greater selectivity by not affecting normal cell growth. Through chemical optimization, we identified several development candidates that selectively inhibit PDE5 and/or PDE10. These compounds activate cGMP/PKG signaling, suppressing Wnt/β-catenin transcription. This action counters the growth advantages resulting from APC or CTNNB1 mutations, which are responsible for most human CRCs. This review delves into the scientific literature supporting PDE5 and/or PDE10 as potential targets for CRC chemoprevention or interception. Our findings suggest a promising avenue for developing drugs that may effectively intervene in the progression of colorectal cancer, offering hope for improved preventive strategies in the future.

Keywords: cGMP; chemoprevention; colorectal cancer; cyclooxygenase; NSAIDs; phosphodiesterase; PKG; sulindac; Wnt; β-catenin;
Copyright: © 2023 by Ramesh, Johnson, Fadlalla, Moore, Huang, Berry, Maxuitenko, Chen, Keeton, Zhou and Piazza. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (Creative Commons Attribution 4.0 International License). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Show Figures

Funding

NIH (R01CA131378) , NIH (R01CA197147) , NIH (R01CA155638) , NIH (R01CA254197) , NIH (R01CA238514)

Share and Cite

ACS Style
Ramesh, S.; Johnson, P.; Fadlalla, K.; Moore, A.; Huang, C.; Berry, K.; Maxuitenko, Y. Y.; Chen, X.; Keeton, A. B.; Zhou, G.; Piazza, G. Novel sulindac derivatives for colorectal cancer chemoprevention that target cGMP phosphodiesterases to suppress Wnt/β-catenin transcriptional activity. Cancer Insight, 2024, 3, 28. https://doi.org/10.58567/ci03010003
AMA Style
Ramesh S, Johnson P, Fadlalla K, Moore A, Huang C, Berry K, Maxuitenko Y Y, Chen X, Keeton A B, Zhou G, Piazza G. Novel sulindac derivatives for colorectal cancer chemoprevention that target cGMP phosphodiesterases to suppress Wnt/β-catenin transcriptional activity. Cancer Insight; 2024, 3(1):28. https://doi.org/10.58567/ci03010003
Chicago/Turabian Style
Ramesh, Sindhu; Johnson, Peyton; Fadlalla, Khalda; Moore, Austin; Huang, Chung-Hui; Berry, Kristy; Maxuitenko, Yulia Y.; Chen, Xi; Keeton, Adam B.; Zhou, Gang, and et al. 2024. "Novel sulindac derivatives for colorectal cancer chemoprevention that target cGMP phosphodiesterases to suppress Wnt/β-catenin transcriptional activity" Cancer Insight 3, no.1:28. https://doi.org/10.58567/ci03010003
APA style
Ramesh, S., Johnson, P., Fadlalla, K., Moore, A., Huang, C., Berry, K., Maxuitenko, Y. Y., Chen, X., Keeton, A. B., Zhou, G., & Piazza, G. (2024). Novel sulindac derivatives for colorectal cancer chemoprevention that target cGMP phosphodiesterases to suppress Wnt/β-catenin transcriptional activity. Cancer Insight, 3(1), 28. https://doi.org/10.58567/ci03010003

Article Metrics

Article Access Statistics

References

  1. Martínez ME, McPherson RS, Levin B, Annegers JF: Aspirin and other nonsteroidal anti-inflammatory drugs and risk of colorectal adenomatous polyps among endoscoped individuals. Cancer Epidemiol Biomarkers Prev 1995, 4(7):703-707. https://pubmed.ncbi.nlm.nih.gov/8672985/
  2. Rosenberg L, Louik C, Shapiro S: Nonsteroidal antiinflammatory drug use and reduced risk of large bowel carcinoma. Cancer 1998, 82(12):2326-2333. https://doi.org/10.1002/(SICI)1097-0142(19980615)82:12%3C2326::AID-CNCR5%3E3.0.CO;2-Q
  3. Muscat JE, Stellman SD, Wynder EL: Nonsteroidal antiinflammatory drugs and colorectal cancer. Cancer 1994, 74(7):1847-1854. https://doi.org/10.1002/1097-0142(19941001)74:7%3C1847::AID-CNCR2820740704%3E3.0.CO;2-%23
  4. Collet JP, Sharpe C, Belzile E, Boivin JF, Hanley J, Abenhaim L: Colorectal cancer prevention by non-steroidal anti-inflammatory drugs: effects of dosage and timing. Br J Cancer 1999, 81(1):62-68. https://doi.org/10.1038/sj.bjc.6690651
  5. Isomäki HA, Hakulinen T, Joutsenlahti U: Excess risk of lymphomas, leukemia and myeloma in patients with rheumatoid arthritis. J Chronic Dis 1978, 31(11):691-696. https://doi.org/10.1016/0021-9681(78)90071-1
  6. Friedman GD, Coates AO, Potter JD, Slattery ML: Drugs and colon cancer. Pharmacoepidemiol Drug Saf 1998, 7(2):99-106. https://doi.org/10.1002/(SICI)1099-1557(199803/04)7:2%3C99::AID-PDS320%3E3.0.CO;2-0
  7. Labayle D, Fischer D, Vielh P, Drouhin F, Pariente A, Bories C, Duhamel O, Trousset M, Attali P: Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 1991, 101(3):635-639. https://doi.org/10.1016/0016-5085(91)90519-Q
  8. Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, Booker SV, Robinson CR, Offerhaus GJ: Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993, 328(18):1313-1316. https://doi.org/10.1056/nejm199305063281805
  9. Gurpinar E, Grizzle WE, Piazza GA: NSAIDs inhibit tumorigenesis, but how? Clin Cancer Res 2014, 20(5):1104-1113. https://doi.org/10.1158/1078-0432.Ccr-13-1573
  10. Piazza GA, Alberts DS, Hixson LJ, Paranka NS, Li H, Finn T, Bogert C, Guillen JM, Brendel K, Gross PH et al: Sulindac Sulfone Inhibits Azoxymethane-induced Colon Carcinogenesis in Rats without Reducing Prostaglandin Levels1. Cancer Research 1997, 57(14):2909-2915. https://pubmed.ncbi.nlm.nih.gov/9230200/
  11. Nugent KP, Farmer KC, Spigelman AD, Williams CB, Phillips RK: Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg 1993, 80(12):1618-1619. https://doi.org/10.1002/bjs.1800801244
  12. Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T et al: The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000, 342(26):1946-1952. https://doi.org/10.1056/nejm200006293422603
  13. Tsujii M, DuBois RN: Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 1995, 83(3):493-501. https://doi.org/10.1016/0092-8674(95)90127-2
  14. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN: Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998, 93(5):705-716. https://doi.org/10.1016/s0092-8674(00)81433-6
  15. Giardiello FM, Offerhaus GJ, DuBois RN: The role of nonsteroidal anti-inflammatory drugs in colorectal cancer prevention. Eur J Cancer 1995, 31a(7-8):1071-1076. https://doi.org/10.1016/0959-8049(95)00137-8
  16. Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, Trzaskos JM, Evans JF, Taketo MM: Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996, 87(5):803-809. https://doi.org/10.1016/s0092-8674(00)81988-1
  17. Reddy BS, Kawamori T, Lubet RA, Steele VE, Kelloff GJ, Rao CV: Chemopreventive efficacy of sulindac sulfone against colon cancer depends on time of administration during carcinogenic process. Cancer Res 1999, 59(14):3387-3391. https://pubmed.ncbi.nlm.nih.gov/10416599/
  18. Wargovich MJ, Jimenez A, McKee K, Steele VE, Velasco M, Woods J, Price R, Gray K, Kelloff GJ: Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression. Carcinogenesis 2000, 21(6):1149-1155. https://doi.org/10.1093/carcin/21.5.149
  19. Thompson HJ, Jiang C, Lu J, Mehta RG, Piazza GA, Paranka NS, Pamukcu R, Ahnen DJ: Sulfone metabolite of sulindac inhibits mammary carcinogenesis. Cancer Res 1997, 57(2):267-271. https://pubmed.ncbi.nlm.nih.gov/9000566/
  20. Malkinson AM, Koski KM, Dwyer-Nield LD, Rice PL, Rioux N, Castonguay A, Ahnen DJ, Thompson H, Pamukcu R, Piazza GA: Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mouse lung tumor formation by FGN-1 (sulindac sulfone). Carcinogenesis 1998, 19(8):1353-1356. https://doi.org/10.1093/carcin/19.8.1353
  21. Piazza GA, Thompson WJ, Pamukcu R, Alila HW, Whitehead CM, Liu L, Fetter JR, Gresh WE, Jr., Klein-Szanto AJ, Farnell DR et al: Exisulind, a Novel Proapoptotic Drug, Inhibits Rat Urinary Bladder Tumorigenesis1. Cancer Research 2001, 61(10):3961-3968. https://pubmed.ncbi.nlm.nih.gov/11358813/
  22. Narayanan BA, Reddy BS, Bosland MC, Nargi D, Horton L, Randolph C, Narayanan NK: Exisulind in combination with celecoxib modulates epidermal growth factor receptor, cyclooxygenase-2, and cyclin D1 against prostate carcinogenesis: in vivo evidence. Clin Cancer Res 2007, 13(19):5965-5973. https://doi.org/10.1158/1078-0432.Ccr-07-0744
  23. McEntee MF, Chiu CH, Whelan J: Relationship of beta-catenin and Bcl-2 expression to sulindac-induced regression of intestinal tumors in Min mice. Carcinogenesis 1999, 20(4):635-640. https://doi.org/10.1093/carcin/20.4.635
  24. He TC, Chan TA, Vogelstein B, Kinzler KW: PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 1999, 99(3):335-345. https://doi.org/10.1016/s0092-8674(00)81664-5
  25. Baek SJ, Kim KS, Nixon JB, Wilson LC, Eling TE: Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities. Mol Pharmacol 2001, 59(4):901-908. https://doi.org/10.1124/MOL.59.4.901
  26. Herrmann C, Block C, Geisen C, Haas K, Weber C, Winde G, Möröy T, Müller O: Sulindac sulfide inhibits Ras signaling. Oncogene 1998, 17(14):1769-1776. https://doi.org/10.1038/sj.onc.1202085
  27. Stark LA, Reid K, Sansom OJ, Din FV, Guichard S, Mayer I, Jodrell DI, Clarke AR, Dunlop MG: Aspirin activates the NF-kappaB signalling pathway and induces apoptosis in intestinal neoplasia in two in vivo models of human colorectal cancer. Carcinogenesis 2007, 28(5):968-976. https://doi.org/10.1093/carcin/bgl220
  28. Boon EMJ, Keller JJ, Wormhoudt TAM, Giardiello FM, Offerhaus GJA, van der Neut R, Pals ST: Sulindac targets nuclear β-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines. British Journal of Cancer 2004, 90(1):224-229. https://doi.org/10.1038/sj.bjc.6601505
  29. Barker N, Clevers H: Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 2006, 5(12):997-1014. https://doi.org/10.1038/nrd2154
  30. Lawson KR, Ignatenko NA, Piazza GA, Cui H, Gerner EW: Influence of K-ras activation on the survival responses of Caco-2 cells to the chemopreventive agents sulindac and difluoromethylornithine. Cancer Epidemiol Biomarkers Prev 2000, 9(11):1155-1162. https://pubmed.ncbi.nlm.nih.gov/11097222/
  31. Rice PL, Kelloff J, Sullivan H, Driggers LJ, Beard KS, Kuwada S, Piazza G, Ahnen DJ: Sulindac metabolites induce caspase- and proteasome-dependent degradation of β-catenin protein in human colon cancer cells. Molecular Cancer Therapeutics 2003, 2(9):885-892. https://pubmed.ncbi.nlm.nih.gov/14555707/
  32. Thompson WJ, Piazza GA, Li H, Liu L, Fetter J, Zhu B, Sperl G, Ahnen D, Pamukcu R: Exisulind induction of apoptosis involves guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin. Cancer Res 2000, 60(13):3338-3342. https://pubmed.ncbi.nlm.nih.gov/10910034/
  33. Yi B, Chang H, Ma R, Feng X, Li W, Piazza GA, Xi Y: Inhibition of breast cancer cell motility with a non-cyclooxygenase inhibitory derivative of sulindac by suppressing TGFβ/miR-21 signaling. Oncotarget 2016, 7(7):7979-7992. https://doi.org/10.18632/oncotarget.6888
  34. Jasperson KW, Tuohy TM, Neklason DW, Burt RW: Hereditary and familial colon cancer. Gastroenterology 2010, 138(6):2044-2058. https://doi.org/10.1053/j.gastro.2010.01.054
  35. Stamos JL, Weis WI: The β-catenin destruction complex. Cold Spring Harb Perspect Biol 2013, 5(1):a007898. https://doi.org/10.1101/cshperspect.a007898
  36. Half E, Bercovich D, Rozen P: Familial adenomatous polyposis. Orphanet J Rare Dis 2009, 4:22. https://doi.org/10.1186/1750-1172-4-22
  37. Bafico A, Liu G, Goldin L, Harris V, Aaronson SA: An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells. Cancer Cell 2004, 6(5):497-506. https://doi.org/10.1016/j.ccr.2004.09.032
  38. Smith G, Carey FA, Beattie J, Wilkie MJ, Lightfoot TJ, Coxhead J, Garner RC, Steele RJ, Wolf CR: Mutations in APC, Kirsten-ras, and p53--alternative genetic pathways to colorectal cancer. Proc Natl Acad Sci USA 2002, 99(14):9433-9438. https://doi.org/10.1073/pnas.122612899
  39. Lynch PM, Ayers GD, Hawk E, Richmond E, Eagle C, Woloj M, Church J, Hasson H, Patterson S, Half E et al: The safety and efficacy of celecoxib in children with familial adenomatous polyposis. Am J Gastroenterol 2010, 105(6):1437-1443. https://doi.org/10.1038/ajg.2009.758
  40. Phillips RK, Wallace MH, Lynch PM, Hawk E, Gordon GB, Saunders BP, Wakabayashi N, Shen Y, Zimmerman S, Godio L et al: A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 2002, 50(6):857-860. https://doi.org/10.1136/gut.50.6.857
  41. Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M: Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005, 352(11):1071-1080. https://doi.org/10.1056/NEJMoa050405
  42. Vane JR, Bakhle YS, Botting RM: Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998, 38:97-120. https://doi.org/10.1146/annurev.pharmtox.38.1.97
  43. Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB, Lipsky PE: Cyclooxygenase in biology and disease. Faseb j 1998, 12(12):1063-1073. https://doi.org/10.1096/fasebj.12.12.1063
  44. Chinery R, Coffey RJ, Graves-Deal R, Kirkland SC, Sanchez SC, Zackert WE, Oates JA, Morrow JD: Prostaglandin J2 and 15-deoxy-delta12,14-prostaglandin J2 induce proliferation of cyclooxygenase-depleted colorectal cancer cells. Cancer Res 1999, 59(11):2739-2746. https://pubmed.ncbi.nlm.nih.gov/10364000/
  45. Sheng H, Shao J, Morrow JD, Beauchamp RD, DuBois RN: Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res 1998, 58(2):362-366. https://pubmed.ncbi.nlm.nih.gov/9443418/
  46. Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, Edwards DA, Flickinger AG, Moore RJ, Seibert K: Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000, 60(5):1306-1311. https://pubmed.ncbi.nlm.nih.gov/10728691/
  47. Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, Boyce SW, Verburg KM: Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005, 352(11):1081-1091. https://doi.org/10.1056/NEJMoa050330
  48. Fitzgerald GA: Coxibs and cardiovascular disease. N Engl J Med 2004, 351(17):1709-1711. https://doi.org/10.1056/NEJMp048288
  49. Elder DJ, Halton DE, Hague A, Paraskeva C: Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug: independence from COX-2 protein expression. Clin Cancer Res 1997, 3(10):1679-1683. https://doi.org/10.0000/PMID9815550
  50. Kusuhara H, Matsuyuki H, Matsuura M, Imayoshi T, Okumoto T, Matsui H: Induction of apoptotic DNA fragmentation by nonsteroidal anti-inflammatory drugs in cultured rat gastric mucosal cells. Eur J Pharmacol 1998, 360(2-3):273-280. https://doi.org/10.1016/s0014-2999(98)00679-7
  51. Hanif R, Pittas A, Feng Y, Koutsos MI, Qiao L, Staiano-Coico L, Shiff SI, Rigas B: Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem Pharmacol 1996, 52(2):237-245. https://doi.org/10.1016/0006-2952(96)00181-5
  52. de Mello MC, Bayer BM, Beaven MA: Evidence that prostaglandins do not have a role in the cytostatic action of anti-inflammatory drugs. Biochem Pharmacol 1980, 29(3):311-318. https://doi.org/10.1016/0006-2952(80)90506-7
  53. Tinsley HN, Gary BD, Thaiparambil J, Li N, Lu W, Li Y, Maxuitenko YY, Keeton AB, Piazza GA: Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition. Cancer Prev Res (Phila) 2010, 3(10):1303-1313. https://doi.org/10.1158/1940-6207.Capr-10-0030
  54. Williams CS, Watson AJ, Sheng H, Helou R, Shao J, DuBois RN: Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models. Cancer Res 2000, 60(21):6045-6051. https://pubmed.ncbi.nlm.nih.gov/11085526/
  55. Stoner GD, Budd GT, Ganapathi R, DeYoung B, Kresty LA, Nitert M, Fryer B, Church JM, Provencher K, Pamukcu R et al: Sulindac sulfone induced regression of rectal polyps in patients with familial adenomatous polyposis. Adv Exp Med Biol 1999, 470:45-53. https://doi.org/10.1007/978-1-4615-4149-3_5
  56. Arber N, Kuwada S, Leshno M, Sjodahl R, Hultcrantz R, Rex D: Sporadic adenomatous polyp regression with exisulind is effective but toxic: a randomised, double blind, placebo controlled, dose-response study. Gut 2006, 55(3):367-373. https://doi.org/10.1136/gut.2004.061432
  57. Piazza GA, Rahm AL, Krutzsch M, Sperl G, Paranka NS, Gross PH, Brendel K, Burt RW, Alberts DS, Pamukcu R et al: Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res 1995, 55(14):3110-3116. https://pubmed.ncbi.nlm.nih.gov/7606732/
  58. Sun W, Stevenson JP, Gallo JM, Redlinger M, Haller D, Algazy K, Giantonio B, Alila H, O'Dwyer PJ: Phase I and pharmacokinetic trial of the proapoptotic sulindac analog CP-461 in patients with advanced cancer. Clin Cancer Res 2002, 8(10):3100-3104. https://scholars.mssm.edu/en/publications/phase-i-and-pharmacokinetic-trial-of-the-proapoptotic-sulindac-an-2
  59. Piazza GA, Keeton AB, Tinsley HN, Gary BD, Whitt JD, Mathew B, Thaiparambil J, Coward L, Gorman G, Li Y et al: A novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits colon tumor cell growth and induces apoptosis with antitumor activity. Cancer Prev Res (Phila) 2009, 2(6):572-580. https://doi.org/10.1158/1940-6207.Capr-09-0001
  60. Zhang Y, Zhang J, Wang L, Quealy E, Gary BD, Reynolds RC, Piazza GA, Lü J: A novel sulindac derivative lacking cyclooxygenase-inhibitory activities suppresses carcinogenesis in the transgenic adenocarcinoma of mouse prostate model. Cancer Prev Res (Phila) 2010, 3(7):885-895. https://doi.org/10.1158/1940-6207.Capr-09-0273
  61. Tinsley HN, Mathew B, Chen X, Maxuitenko YY, Li N, Lowe WM, Whitt JD, Zhang W, Gary BD, Keeton AB et al: Novel Non-Cyclooxygenase Inhibitory Derivative of Sulindac Inhibits Breast Cancer Cell Growth In Vitro and Reduces Mammary Tumorigenesis in Rats. Cancers 2023, 15(3):646. https://www.mdpi.com/2072-6694/15/3/646
  62. Tinsley HN, Gary BD, Keeton AB, Lu W, Li Y, Piazza GA: Inhibition of PDE5 by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt/β-catenin-mediated transcription in human breast tumor cells. Cancer Prev Res (Phila) 2011, 4(8):1275-1284. https://doi.org/10.1158/1940-6207.Capr-11-0095
  63. Whitt JD, Li N, Tinsley HN, Chen X, Zhang W, Li Y, Gary BD, Keeton AB, Xi Y, Abadi AH et al: A novel sulindac derivative that potently suppresses colon tumor cell growth by inhibiting cGMP phosphodiesterase and β-catenin transcriptional activity. Cancer Prev Res (Phila) 2012, 5(6):822-833. https://doi.org/10.1158/1940-6207.Capr-11-0559
  64. Piazza GA, Ward A, Chen X, Maxuitenko Y, Coley A, Aboelella NS, Buchsbaum DJ, Boyd MR, Keeton AB, Zhou G: PDE5 and PDE10 inhibition activates cGMP/PKG signaling to block Wnt/β-catenin transcription, cancer cell growth, and tumor immunity. Drug Discov Today 2020, 25(8):1521-1527. https://doi.org/10.1016/j.drudis.2020.06.008
  65. Li N, Xi Y, Tinsley HN, Gurpinar E, Gary BD, Zhu B, Li Y, Chen X, Keeton AB, Abadi AH et al: Sulindac selectively inhibits colon tumor cell growth by activating the cGMP/PKG pathway to suppress Wnt/β-catenin signaling. Mol Cancer Ther 2013, 12(9):1848-1859. https://doi.org/10.1158/1535-7163.Mct-13-0048
  66. Mei XL, Yang Y, Zhang YJ, Li Y, Zhao JM, Qiu JG, Zhang WJ, Jiang QW, Xue YQ, Zheng DW et al: Sildenafil inhibits the growth of human colorectal cancer in vitro and in vivo. Am J Cancer Res 2015, 5(11):3311-3324. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697679/
  67. Shi Z, Tiwari AK, Shukla S, Robey RW, Singh S, Kim IW, Bates SE, Peng X, Abraham I, Ambudkar SV et al: Sildenafil reverses ABCB1- and ABCG2-mediated chemotherapeutic drug resistance. Cancer Res 2011, 71(8):3029-3041. https://doi.org/10.1158/0008-5472.Can-10-3820
  68. Lin S, Wang J, Wang L, Wen J, Guo Y, Qiao W, Zhou J, Xu G, Zhi F: Phosphodiesterase-5 inhibition suppresses colonic inflammation-induced tumorigenesis via blocking the recruitment of MDSC. Am J Cancer Res 2017, 7(1):41-52. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5250679/
  69. Islam BN, Sharman SK, Hou Y, Bridges AE, Singh N, Kim S, Kolhe R, Trillo-Tinoco J, Rodriguez PC, Berger FG et al: Sildenafil Suppresses Inflammation-Driven Colorectal Cancer in Mice. Cancer Prev Res (Phila) 2017, 10(7):377-388. https://doi.org/10.1158/1940-6207.Capr-17-0015
  70. Huang W, Sundquist J, Sundquist K, Ji J: Use of Phosphodiesterase 5 Inhibitors Is Associated With Lower Risk of Colorectal Cancer in Men With Benign Colorectal Neoplasms. Gastroenterology 2019, 157(3):672-681.e674. https://doi.org/10.1053/j.gastro.2019.05.012
  71. Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, Dolcetti L, Bronte V, Borrello I: Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 2006, 203(12):2691-2702. https://doi.org/10.1084/jem.20061104
  72. Noonan KA, Ghosh N, Rudraraju L, Bui M, Borrello I: Targeting immune suppression with PDE5 inhibition in end-stage multiple myeloma. Cancer Immunol Res 2014, 2(8):725-731. https://doi.org/10.1158/2326-6066.Cir-13-0213
  73. Weed DT, Vella JL, Reis IM, De la Fuente AC, Gomez C, Sargi Z, Nazarian R, Califano J, Borrello I, Serafini P: Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res 2015, 21(1):39-48. https://doi.org/10.1158/1078-0432.Ccr-14-1711
  74. Soderling SH, Bayuga SJ, Beavo JA: Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A. Proc Natl Acad Sci U S A 1999, 96(12):7071-7076. https://doi.org/10.1073/pnas.96.12.7071
  75. Omori K, Kotera J: Overview of PDEs and their regulation. Circ Res 2007, 100(3):309-327. https://doi.org/10.1161/01.RES.0000256354.95791.f1
  76. Fujishige K, Kotera J, Michibata H, Yuasa K, Takebayashi S, Okumura K, Omori K: Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A). J Biol Chem 1999, 274(26):18438-18445. https://doi.org/10.1074/jbc.274.26.18438
  77. Seeger TF, Bartlett B, Coskran TM, Culp JS, James LC, Krull DL, Lanfear J, Ryan AM, Schmidt CJ, Strick CA et al: Immunohistochemical localization of PDE10A in the rat brain. Brain Res 2003, 985(2):113-126. https://doi.org/10.1016/s0006-8993(03)02754-9
  78. Wagner S, Teodoro R, Deuther-Conrad W, Kranz M, Scheunemann M, Fischer S, Wenzel B, Egerland U, Hoefgen N, Steinbach J et al: Radiosynthesis and biological evaluation of the new PDE10A radioligand [18F]AQ28A. Journal of Labelled Compounds and Radiopharmaceuticals 2017, 60(1):36-48. https://doi.org/ 10.1002/jlcr.3471
  79. Siuciak JA, Chapin DS, Harms JF, Lebel LA, McCarthy SA, Chambers L, Shrikhande A, Wong S, Menniti FS, Schmidt CJ: Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis. Neuropharmacology 2006, 51(2):386-396. https://doi.org/10.1016/j.neuropharm.2006.04.013
  80. Jäger R, Russwurm C, Schwede F, Genieser HG, Koesling D, Russwurm M: Activation of PDE10 and PDE11 phosphodiesterases. J Biol Chem 2012, 287(2):1210-1219. https://doi.org/10.1074/jbc.M111.263806
  81. Li N, Lee K, Xi Y, Zhu B, Gary BD, Ramírez-Alcántara V, Gurpinar E, Canzoneri JC, Fajardo A, Sigler S et al: Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and β-catenin-dependent TCF transcriptional activity. Oncogene 2015, 34(12):1499-1509. https://doi.org/10.1038/onc.2014.94
  82. Zhu B, Lindsey A, Li N, Lee K, Ramirez-Alcantara V, Canzoneri JC, Fajardo A, Madeira da Silva L, Thomas M, Piazza JT et al: Phosphodiesterase 10A is overexpressed in lung tumor cells and inhibitors selectively suppress growth by blocking β-catenin and MAPK signaling. Oncotarget 2017, 8(41):69264-69280. https://doi.org/10.18632/oncotarget.20566
  83. Lee K, Lindsey AS, Li N, Gary B, Andrews J, Keeton AB, Piazza GA: β-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. Oncotarget 2016, 7(5):5353-5365. https://doi.org/10.18632/oncotarget.6705
  84. Lee KJ, Chang WL, Chen X, Valiyaveettil J, Ramirez-Alcantara V, Gavin E, Musiyenko A, Madeira da Silva L, Annamdevula NS, Leavesley SJ et al: Suppression of Colon Tumorigenesis in Mutant Apc Mice by a Novel PDE10 Inhibitor that Reduces Oncogenic β-Catenin. Cancer Prev Res (Phila) 2021, 14(11):995-1008. https://doi.org/10.1158/1940-6207.Capr-21-0208
  85. Spranger S, Bao R, Gajewski TF: Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015, 523(7559):231-235. https://doi.org/10.1038/nature14404
  86. Spranger S, Dai D, Horton B, Gajewski TF: Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. Cancer Cell 2017, 31(5):711-723.e714. https://doi.org/10.1016/j.ccell.2017.04.003
  87. Borneman RM, Gavin E, Musiyenko A, Richter W, Lee KJ, Crossman DK, Andrews JF, Wilhite AM, McClellan S, Aragon I et al: Phosphodiesterase 10A (PDE10A) as a novel target to suppress β-catenin and RAS signaling in epithelial ovarian cancer. Journal of Ovarian Research 2022, 15(1):120. https://doi.org/10.1186/s13048-022-01050-9
  88. Cho K-j, van der Hoeven D, Zhou Y, Maekawa M, Ma X, Chen W, Fairn GD, Hancock JF: Inhibition of Acid Sphingomyelinase Depletes Cellular Phosphatidylserine and Mislocalizes K-Ras from the Plasma Membrane. Molecular and Cellular Biology 2016, 36(2):363-374. https://doi.org/10.1128/MCB.00719-15
  89. Li N, Chen X, Zhu B, Ramírez-Alcántara V, Canzoneri JC, Lee K, Sigler S, Gary B, Li Y, Zhang W et al: Suppression of β-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10. Oncotarget 2015, 6(29):27403-27415. https://doi.org/10.18632/oncotarget.4741