Carcinogenesis, Vol 19, 87-91, Copyright © 1998 by Oxford University Press
NN Mahmoud, SK Boolbol, AJ Dannenberg, JR Mestre, RT Bilinski, C Martucci, HL Newmark, A Chadburn and MM Bertagnolli
Sulindac, a non-steroidal anti-inflammatory drug (NSAID), is effective in
treating intestinal adenomas in humans with Familial Adenomatous Polyposis
(FAP) and in preventing intestinal tumors in the C57Bl/6J- Min+ (Min)
mouse, an animal model of FAP. Sulindac is a prodrug metabolized by the
liver and intestinal flora to a sulfone, which has no anti-inflammatory
activity, and a sulfide, which is the active anti- inflammatory metabolite.
In this study, we determined which of these metabolites is responsible for
the anti-tumor effect of sulindac in Min mice. Min mice were treated with
either sulindac sulfone or sulindac sulfide (0.5 +/- 0.1 mg/day). Min mice
and homozygous C57Bl/6J-(+/+) normal litter-mates lacking the Apc mutation
(+/+) were used as controls. At 110 days of age, all mice were euthanized
and their intestinal tracts examined. Control Min mice had 33.2 +/- 6.6
tumors per mouse compared to 0.6 +/- 0.3 tumors for sulindac
sulfide-treated Min mice (P < 0.001) and 21.9 +/- 4.5 tumors per mouse
for sulindac sulfone-treated Min mice (P > 0.05). Decreased enterocyte
apoptosis was observed in Min control mice and Min mice treated with
sulindac sulfone. Sulindac sulfide restored to normal the level of
apoptosis in the mucosa of Min animals and decreased levels of PGE2 in the
small intestine of treated Min animals by 59% (P < 0.001). These data
suggest that the anti-tumor effect of sulindac in Apc-deficient animals is
mediated by the sulfide metabolite and correlates with suppression of
tissue prostaglandin synthesis.
ARTICLES
The sulfide metabolite of sulindac prevents tumors and restores enterocyte apoptosis in a murine model of familial adenomatous polyposis
The New York Hospital-Cornell University Medical Center, NY 10021, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Guillen-Ahlers, S. A. Buechler, M. A. Suckow, F. J. Castellino, and V. A. Ploplis Sulindac treatment alters collagen and matrilysin expression in adenomas of ApcMin/+ mice Carcinogenesis, July 1, 2008; 29(7): 1421 - 1427. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Sporn and W. K. Hong Clinical Prevention of Recurrence of Colorectal Adenomas by the Combination of Difluoromethylornithine and Sulindac: An Important Milestone Cancer Prevention Research, June 1, 2008; 1(1): 9 - 11. [Full Text] [PDF]
|
|
|
|
 |
|
 T. O. Keku, A. Amin, J. Galanko, C. Martin, B. Schliebe, and R. S. Sandler Apoptosis in Normal Rectal Mucosa, Baseline Adenoma Characteristics, and Risk of Future Adenomas Cancer Epidemiol. Biomarkers Prev., February 1, 2008; 17(2): 306 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Eisinger, L. D. Nadauld, D. N. Shelton, P. W. Peterson, R. A. Phelps, S. Chidester, D. M. Stafforini, S. M. Prescott, and D. A. Jones The Adenomatous Polyposis Coli Tumor Suppressor Gene Regulates Expression of Cyclooxygenase-2 by a Mechanism That Involves Retinoic Acid J. Biol. Chem., July 21, 2006; 281(29): 20474 - 20482. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Sinicrope and R. C. Penington Sulindac sulfide-induced apoptosis is enhanced by a small-molecule Bcl-2 inhibitor and by TRAIL in human colon cancer cells overexpressing Bcl-2 Mol. Cancer Ther., October 1, 2005; 4(10): 1475 - 1483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Koornstra, F. E.M. Rijcken, C. N.A.M. Oldenhuis, N. Zwart, T. van der Sluis, H. Hollema, E. G.E. deVries, J. J. Keller, J. A. Offerhaus, F. M. Giardiello, et al. Sulindac Inhibits {beta}-Catenin Expression in Normal-Appearing Colon of Hereditary Nonpolyposis Colorectal Cancer and Familial Adenomatous Polyposis Patients Cancer Epidemiol. Biomarkers Prev., July 1, 2005; 14(7): 1608 - 1612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Javid, A. E. Moran, A. M. Carothers, M. Redston, and M. M. Bertagnolli Modulation of tumor formation and intestinal cell migration by estrogens in the ApcMin/+ mouse model of colorectal cancer Carcinogenesis, March 1, 2005; 26(3): 587 - 595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Tsuneoka, Y. Tajima, A. Kitazato, K. Fukuda, T. Kitajima, T. Kuroki, S. Onizuka, and T. Kanematsu Chemopreventative effect of a cyclooxygenase-2-specific inhibitor (etodolac) on chemically induced biliary carcinogenesis in hamsters Carcinogenesis, February 1, 2005; 26(2): 465 - 469. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sun and F. A. Sinicrope Selective inhibitors of MEK1/ERK44/42 and p38 mitogen-activated protein kinases potentiate apoptosis induction by sulindac sulfide in human colon carcinoma cells Mol. Cancer Ther., January 1, 2005; 4(1): 51 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Moran, D. H. Hunt, S. H. Javid, M. Redston, A. M. Carothers, and M. M. Bertagnolli Apc Deficiency Is Associated with Increased Egfr Activity in the Intestinal Enterocytes and Adenomas of C57BL/6J-Min/+ Mice J. Biol. Chem., October 8, 2004; 279(41): 43261 - 43272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Pozzi, X. Yan, I. Macias-Perez, S. Wei, A. N. Hata, R. M. Breyer, J. D. Morrow, and J. H. Capdevila Colon Carcinoma Cell Growth Is Associated with Prostaglandin E2/EP4 Receptor-evoked ERK Activation J. Biol. Chem., July 9, 2004; 279(28): 29797 - 29804. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. Sinicrope, E. Half, J. S. Morris, P. M. Lynch, J. D. Morrow, B. Levin, E. T. Hawk, D. S. Cohen, G. D. Ayers, and L. C. Stephens Cell Proliferation and Apoptotic Indices Predict Adenoma Regression in a Placebo-Controlled Trial of Celecoxib in Familial Adenomatous Polyposis Patients Cancer Epidemiol. Biomarkers Prev., June 1, 2004; 13(6): 920 - 927. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. G. Bottone Jr, J. M. Martinez, B. Alston-Mills, and T. E. Eling Gene modulation by Cox-1 and Cox-2 specific inhibitors in human colorectal carcinoma cancer cells Carcinogenesis, March 1, 2004; 25(3): 349 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. L. Rice, J. Kelloff, H. Sullivan, L. J. Driggers, K. S. Beard, S. Kuwada, G. Piazza, and D. J. Ahnen Sulindac metabolites induce caspase- and proteasome-dependent degradation of {beta}-catenin protein in human colon cancer cells Mol. Cancer Ther., September 1, 2003; 2(9): 885 - 892. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. L. Kettunen, A. S. L. Kettunen, and N. E. Rautonen Intestinal Immune Responses in Wild-Type and ApcMin/+ Mouse, a Model for Colon Cancer Cancer Res., August 15, 2003; 63(16): 5136 - 5142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sun, X. M. Tang, E. Half, M. T. Kuo, and F. A. Sinicrope Cyclooxygenase-2 Overexpression Reduces Apoptotic Susceptibility by Inhibiting the Cytochrome c-dependent Apoptotic Pathway in Human Colon Cancer Cells Cancer Res., November 1, 2002; 62(21): 6323 - 6328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Tang, Y. J. Sun, E. Half, M. T. Kuo, and F. Sinicrope Cyclooxygenase-2 Overexpression Inhibits Death Receptor 5 Expression and Confers Resistance to Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Colon Cancer Cells Cancer Res., September 1, 2002; 62(17): 4903 - 4908. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Lippman and W. Ki Hong Cancer Prevention by Delay : Commentary re: J. A. O'Shaughnessy et al., Treatment and Prevention of Intraepithelial Neoplasia: An Important Target for Accelerated New Agent Development. Clin. Cancer Res., 8: 314-346, 2002. Clin. Cancer Res., February 1, 2002; 8(2): 305 - 313. [Full Text] [PDF]
|
|
|
|
|
|
G. Lal, C. Ash, K. Hay, M. Redston, E. Kwong, B. Hancock, T. Mak, S. Kargman, J. F. Evans, and S. Gallinger Suppression of Intestinal Polyps in Msh2-deficient and Non-Msh2-deficient Multiple Intestinal Neoplasia Mice by a Specific Cyclooxygenase-2 Inhibitor and by a Dual Cyclooxygenase-1/2 Inhibitor Cancer Res., August 1, 2001; 61(16): 6131 - 6136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Krishnan, M. T. Ruffin, D. Normolle, I. Shureiqi, K. Burney, J. Bailey, M. Peters-Golden, C. L. Rock, C. R. Boland, and D. E. Brenner Colonic Mucosal Prostaglandin E2 and Cyclooxygenase Expression before and after Low Aspirin Doses in Subjects at High Risk or at Normal Risk for Colorectal Cancer Cancer Epidemiol. Biomarkers Prev., May 1, 2001; 10(5): 447 - 453. [Abstract] [Full Text]
|
|
|
|
|
|
M. J. Weyant, A. M. Carothers, N. N. Mahmoud, H. L. Bradlow, H. Remotti, R. T. Bilinski, and M. M. Bertagnolli Reciprocal Expression of ER{{alpha}} and ER{beta} Is Associated with Estrogen-mediated Modulation of Intestinal Tumorigenesis Cancer Res., March 1, 2001; 61(6): 2547 - 2551. [Abstract] [Full Text]
|
|
|
|
|
|
M. Oshima, N. Murai, S. Kargman, M. Arguello, P. Luk, E. Kwong, M. M. Taketo, and J. F. Evans Chemoprevention of Intestinal Polyposis in the Apc{{Delta}}716 Mouse by Rofecoxib, a Specific Cyclooxygenase-2 Inhibitor Cancer Res., February 1, 2001; 61(4): 1733 - 1740. [Abstract] [Full Text]
|
|
|
|
|
|
M. J. Weyant, A. M. Carothers, A. J. Dannenberg, and M. M. Bertagnolli (+)-Catechin Inhibits Intestinal Tumor Formation and Suppresses Focal Adhesion Kinase Activation in the Min/+ Mouse Cancer Res., January 1, 2001; 61(1): 118 - 125. [Abstract] [Full Text]
|
|
|
|
|
|
C. S. Williams, A. J. M. Watson, H. Sheng, R. Helou, J. Shao, and R. N. DuBois Celecoxib Prevents Tumor Growth in Vivo without Toxicity to Normal Gut: Lack of Correlation between in Vitro and in Vivo Models Cancer Res., November 1, 2000; 60(21): 6045 - 6051. [Abstract] [Full Text]
|
|
|
|
|
|
K. Yang, S. A. Lamprecht, Y. Liu, H. Shinozaki, K. Fan, D. Leung, H. Newmark, V. E. Steele, G. J. Kelloff, and M. Lipkin Chemoprevention studies of the flavonoids quercetin and rutin in normal and azoxymethane-treated mouse colon Carcinogenesis, September 1, 2000; 21(9): 1655 - 1660. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. T. Cormier and W. F. Dove Dnmt1N/+ Reduces the Net Growth Rate and Multiplicity of Intestinal Adenomas in C57BL/6-Multiple Intestinal Neoplasia (Min)/+ Mice Independently of p53 but Demonstrates Strong Synergy with the Modifier of Min 1AKR Resistance Allele Cancer Res., July 1, 2000; 60(14): 3965 - 3970. [Abstract] [Full Text]
|
|
|
|
 |
|
 K. H. Goss and J. Groden Biology of the Adenomatous Polyposis Coli Tumor Suppressor J. Clin. Oncol., May 9, 2000; 18(9): 1967 - 1979. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Weyant, A. M. Carothers, M. E. Bertagnolli, and M. M. Bertagnolli Colon Cancer Chemopreventive Drugs Modulate Integrin-mediated Signaling Pathways Clin. Cancer Res., March 1, 2000; 6(3): 949 - 956. [Abstract] [Full Text]
|
|
|
|
 |
|
 T. A. de Jong, S. A. Skinner, C. Malcontenti-Wilson, D. Vogiagis, M. Bailey, I. R. van Driel, and P. E. O'Brien Inhibition of rat colon tumors by sulindac and sulindac sulfone is independent of K-ras (codon 12) mutation Am J Physiol Gastrointest Liver Physiol, February 1, 2000; 278(2): G266 - G272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. van Stolk, G. Stoner, W. L. Hayton, K. Chan, B. DeYoung, L. Kresty, B. H. Kemmenoe, P. Elson, L. Rybicki, J. Church, et al. Phase I Trial of Exisulind (Sulindac Sulfone, FGN-1) as a Chemopreventive Agent in Patients with Familial Adenomatous Polyposis Clin. Cancer Res., January 1, 2000; 6(1): 78 - 89. [Abstract] [Full Text]
|
|
|
|
|
|
L. H. Augenlicht, G. M. Anthony, T. L. Church, W. Edelmann, R. Kucherlapati, K. Yang, M. Lipkin, and B. G. Heerdt Short-Chain Fatty Acid Metabolism, Apoptosis, and Apc-initiated Tumorigenesis in the Mouse Gastrointestinal Mucosa Cancer Res., December 1, 1999; 59(23): 6005 - 6009. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. H. Augenlicht and M. M. Bertagnolli Correspondence re: N. N. Mahmoud et al., Genotype-Phenotype Correlation in Murine Apc Mutation: Differences in Enterocyte Migration and Response to Sulindac. Cancer Res., 59: 353-359, 1999. Cancer Res., November 1, 1999; 59(22): 5856 - 5857. [Full Text] [PDF]
|
|
|
|
|
|
Y. Yamamoto, M.-J. Yin, K.-M. Lin, and R. B. Gaynor Sulindac Inhibits Activation of the NF-kappa B Pathway J. Biol. Chem., September 17, 1999; 274(38): 27307 - 27314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. S. Reddy, T. Kawamori, R. A. Lubet, V. E. Steele, G. J. Kelloff, and C. V. Rao Chemopreventive Efficacy of Sulindac Sulfone against Colon Cancer Depends on Time of Administration during Carcinogenic Process Cancer Res., July 1, 1999; 59(14): 3387 - 3391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Barnes, R. L. Hamby-Mason, W. E. Hardman, I. L. Cameron, K. V. Speeg, and M. Lee Effect of Aspirin on Prostaglandin E2 Formation and Transforming Growth Factor {alpha} Expression in Human Rectal Mucosa from Individuals with a History of Adenomatous Polyps of the Colon1 Cancer Epidemiol. Biomarkers Prev., April 1, 1999; 8(4): 311 - 315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. N. Mahmoud, A. J. Dannenberg, R. T. Bilinski, J. R. Mestre, A. Chadburn, M. Churchill, C. Martucci, and M. M. Bertagnolli Administration of an unconjugated bile acid increases duodenal tumors in a murine model of familial adenomatous polyposis Carcinogenesis, February 1, 1999; 20(2): 299 - 303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. N. Mahmoud, R. T. Bilinski, M. R. Churchill, W. Edelmann, R. Kucherlapati, and M. M. Bertagnolli Genotype-Phenotype Correlation in Murine Apc Mutation: Differences in Enterocyte Migration and Response to Sulindac Cancer Res., January 1, 1999; 59(2): 353 - 359. [Abstract] [Full Text] [PDF]
|
|