Combination of Sulindac and Bexarotene for Prevention of Intestinal Carcinogenesis in Familial Adenomatous Polyposis.
Adenomatous Polyposis Coli
/ drug therapy
Adenomatous Polyps
/ drug therapy
Adult
Animals
Anti-Inflammatory Agents, Non-Steroidal
/ administration & dosage
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Bexarotene
/ administration & dosage
Carcinogenesis
/ drug effects
Case-Control Studies
Cells, Cultured
Female
Gene Expression Regulation, Neoplastic
/ drug effects
HCT116 Cells
HT29 Cells
Humans
Intestinal Neoplasms
/ genetics
Male
Mice
Mice, Transgenic
Sulindac
/ administration & dosage
Journal
Cancer prevention research (Philadelphia, Pa.)
ISSN: 1940-6215
Titre abrégé: Cancer Prev Res (Phila)
Pays: United States
ID NLM: 101479409
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
22
09
2020
revised:
23
02
2021
accepted:
25
05
2021
pubmed:
17
7
2021
medline:
29
3
2022
entrez:
16
7
2021
Statut:
ppublish
Résumé
Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome, which results in the development of hundreds of adenomatous polyps carpeting the gastrointestinal tract. NSAIDs have reduced polyp burden in patients with FAP and synthetic rexinoids have demonstrated the ability to modulate cytokine-mediated inflammation and WNT signaling. This study examined the use of the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach for reducing FAP colonic polyposis to prevent colorectal cancer development. Whole transcriptomic analysis of colorectal polyps and matched normal mucosa in a cohort of patients with FAP to identify potential targets for prevention in FAP was performed. Drug-dose synergism of sulindac and bexarotene in cell lines and patient-derived organoids was assessed, and the drug combination was tested in two different mouse models. This work explored mRNA as a potential predictive serum biomarker for this combination in FAP. Overall, transcriptomic analysis revealed significant activation of inflammatory and cell proliferation pathways. A synergistic effect of sulindac (300 μmol/L) and bexarotene (40 μmol/L) was observed in FAP colonic organoids with primary targeting of polyp tissue compared with normal mucosa. This combination translated into a significant reduction in polyp development in
Identifiants
pubmed: 34266857
pii: 1940-6207.CAPR-20-0496
doi: 10.1158/1940-6207.CAPR-20-0496
pmc: PMC8416926
mid: NIHMS1726535
doi:
Substances chimiques
Anti-Inflammatory Agents, Non-Steroidal
0
Sulindac
184SNS8VUH
Bexarotene
A61RXM4375
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
851-862Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Informations de copyright
©2021 American Association for Cancer Research.
Références
Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1521-6
pubmed: 11818567
N Engl J Med. 1993 May 6;328(18):1313-6
pubmed: 8385741
Carcinogenesis. 2009 Mar;30(3):377-86
pubmed: 19136477
Cancer Prev Res (Phila). 2018 Jan;11(1):4-15
pubmed: 29109117
Oncol Rep. 2012 May;27(5):1400-6
pubmed: 22307264
J Biol Chem. 2006 Jul 21;281(29):20474-82
pubmed: 16699180
Oncogene. 2011 Jul 21;30(29):3234-47
pubmed: 21383692
Inflamm Bowel Dis. 2006 Nov;12(11):1025-35
pubmed: 17075343
Mol Med Rep. 2015 Oct;12(4):5407-14
pubmed: 26151111
Gut. 2007 Mar;56(3):417-25
pubmed: 16840506
Lancet Oncol. 2013 Dec;14(13):1295-306
pubmed: 24239208
N Engl J Med. 2002 Apr 4;346(14):1054-9
pubmed: 11932472
Carcinogenesis. 1996 Aug;17(8):1757-60
pubmed: 8761438
Gastroenterology. 2004 Feb;126(2):425-31
pubmed: 14762779
Neoplasia. 2012 Feb;14(2):159-68
pubmed: 22431924
Cancer Res. 2005 Apr 15;65(8):3462-9
pubmed: 15833882
Nat Med. 2015 Nov;21(11):1350-6
pubmed: 26457759
Nat Med. 2009 Jun;15(6):701-6
pubmed: 19398967
Gastroenterology. 2011 Nov;141(5):1762-72
pubmed: 21889923
Cancer Prev Res (Phila). 2011 Nov;4(11):1728-35
pubmed: 21778329
Carcinogenesis. 2015 Mar;36(3):338-45
pubmed: 25503932
J Pathol. 2019 Apr;247(5):574-588
pubmed: 30584801
CA Cancer J Clin. 2020 Jan;70(1):7-30
pubmed: 31912902
Oncogene. 2010 Feb 11;29(6):781-8
pubmed: 19946329
Gastroenterology. 2011 Oct;141(4):1486-97, 1497.e1-14
pubmed: 21704588
Nat Commun. 2014 Mar 26;5:3543
pubmed: 24667544
J Cell Physiol. 2019 Jun;234(6):8075-8081
pubmed: 30317621
Cancer Cell. 2010 Jun 15;17(6):560-73
pubmed: 20541701
JAMA Oncol. 2018 May 1;4(5):671-677
pubmed: 29423501
BMC Cancer. 2011 Jun 13;11:238
pubmed: 21668942
Mol Cell Biochem. 2019 Apr;454(1-2):177-189
pubmed: 30357530
Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):657-62
pubmed: 9012840
Nature. 2012 Jul 18;487(7407):330-7
pubmed: 22810696
Clin Cancer Res. 2016 Aug 1;22(15):3841-8
pubmed: 26957558
Dis Model Mech. 2017 Mar 1;10(3):197-214
pubmed: 28250048
Nat Rev Gastroenterol Hepatol. 2016 Jun;13(6):352-61
pubmed: 27095653
N Engl J Med. 2000 Jun 29;342(26):1946-52
pubmed: 10874062
Nat Rev Cancer. 2010 Mar;10(3):181-93
pubmed: 20168319
Sci Rep. 2017 Jul 6;7(1):4770
pubmed: 28684780
Am J Gastroenterol. 2015 Feb;110(2):223-62; quiz 263
pubmed: 25645574
JAMA Oncol. 2018 Aug 1;4(8):1085-1092
pubmed: 29710228
Cell Stem Cell. 2016 Jun 2;18(6):827-838
pubmed: 27212702
Mol Cancer Ther. 2008 Jan;7(1):181-90
pubmed: 18202021
Anticancer Res. 2007 Nov-Dec;27(6A):3729-34
pubmed: 17970035
J Clin Invest. 2004 Dec;114(11):1676-85
pubmed: 15578100
Gastroenterology. 2010 Jun;138(6):2044-58
pubmed: 20420945
Cancer Res. 2007 Oct 15;67(20):9721-30
pubmed: 17942902
Cancer Prev Res (Phila). 2013 Dec;6(12):1251-61
pubmed: 24080207
Nat Med. 2017 Jul;23(7):878-884
pubmed: 28628110