Sulindac causes regression of rectal polyps in familial adenomatous polyposis

Labayle, D; Fischer, D; Vielh, Philippe; Drouhin, F; Pariente, A; Bories, Christian; Duhamel, Olivier; M, Trousset; Attali, P

doi:10.1016/0016-5085(91)90519-q

Cited by 620 publications

(271 citation statements)

References 14 publications

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“…Case series and many randomized controlled trials have confirmed this observation for nonselective NSAIDs such as sulindac (2)(3)(4)(5)(6). However, the gastrointestinal toxicity of nonselective NSAIDs led to the development of selective COX-2 inhibitors.…”

Section: Introductionmentioning

confidence: 96%

A Phase Ib Study of the Effects of Black Raspberries on Rectal Polyps in Patients with Familial Adenomatous Polyposis

Wang¹,

Burke

Hasson

et al. 2014

Cancer Prevention Research

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Familial adenomatous polyposis (FAP) is characterized by the early onset of colonic polyposis and a high risk for colorectal cancer. FAP is treated by colectomy followed by lifelong removal of rectal polyps. This study determined whether black raspberries (BRBs) might regress rectal polyps in patients with FAP. Fourteen patients with FAP were treated with BRBs daily for 9 months. Seven patients received BRB powder orally plus two BRB suppositories inserted into the rectum at bedtime. The other 7 received an oral placebo plus the suppositories. Rectal polyp counts and polyp sizes were obtained at time zero and after 9 months of BRB treatment. Polyps and adjacent normal tissue were collected at both time points. The burden (P ¼ 0.036) but not number (P ¼ 0.069) of rectal polyps was significantly decreased. No benefit was noted with the addition of oral BRBs. Three patients were nonresponders. BRBs significantly decreased cellular proliferation, DNA methylation methyl transferase 1 protein expression, and p16 promoter methylation, but not promoter methylation of the Wnt pathway antagonists, SFRP2 and WIF1, in rectal polyps (adenomas) from responders but not from nonresponders. The MBD-seq assay revealed more demethylated transcription start sites (TSS), including those for miRNAs, in BRB-treated adenomas from the responders. In conclusion, BRB suppositories seem sufficient for regressing rectal polyps in patients with FAP. Cancer Prev Res; 7(7); 666-74. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 96%

A Phase Ib Study of the Effects of Black Raspberries on Rectal Polyps in Patients with Familial Adenomatous Polyposis

Wang¹,

Burke

Hasson

et al. 2014

Cancer Prevention Research

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“…Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce death rates due to colon cancer (Thun et al, 1991) and to reduce the size of colonic adenomatous polyps (Labayle et al, 1991), both in animal and in human studies (Husain et al, 2002 and references therein). These findings suggest that chemoprevention of colon cancer may be a possible way of reducing the impact of this increasingly common and frequently fatal disease.…”

Section: Introductionmentioning

confidence: 99%

Effect of aspirin on the Wnt/β-catenin pathway is mediated via protein phosphatase 2A

et al. 2006

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Nonsteroidal anti-inflammatory drugs show chemopreventive efficacy in colon cancer, but the mechanism behind this remains unclear. Elucidating this mechanism is seen as vital to the development of new chemopreventive agents. We studied the effects of aspirin on the oncogenic Wnt/b-catenin pathway activity in colorectal cancer cell lines and observed that aspirin dose-dependently decreased the activity of this pathway, as judged by TCF-driven luciferase activity, reduced Wnt target gene expression and increased phosphorylation of b-catenin by immunoblotting. Furthermore, the ubiquitination and cytoplasmic levels of b-catenin were assessed by immunoblotting, and also the localization of b-catenin was shown by green fluorescent protein-tagged b-catenin and time-lapse fluorescent imaging. Importantly, aspirin treatment caused increased phosphorylation of protein phosphatase 2A (PP2A), an event associated with inhibition of PP2A enzymatic activity, which was confirmed by a reduction in enzymatic PP2A activity. Moreover, this inhibition of PP2A enzymatic activity was essential for the effects of aspirin on the Wnt/b-catenin pathway as shown by transient transfection with PP2A constructs. The findings in this article provide a molecular explanation for the efficacy of aspirin in chemoprevention of colorectal cancer and shows biochemical evidence that PP2A is an important regulator of Wnt/b-catenin pathway activity in these cells.

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“…In addition, a specific class of chemopreventive drugs known as the non-steroidal anti-inflammatory drugs (NSAIDs), which have been reported to cause regression of polyps in both humans and animals (15)(16)(17), is believed to primarily mediate its anti-neoplastic effects by inhibiting prostanoid biosynthesis at the level of cyclooxygenase (Cox)-2. However, a number of recent studies indicate that Cox-2-independent mechanism(s) are likely also involved in this process.…”

Section: Introductionmentioning

confidence: 99%

Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide

Marotta

Parhar²,

Hundal³

et al. 2006

Int J Oncol

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Abstract. Non-steroidal anti-inflammatory drugs such as sulindac inhibit human colorectal carcinogenesis through a mechanism involving the direct inhibition of cyclooxygenase (Cox)-2. However, a wealth of recent evidence indicates that these agents might elicit their effects through mechanisms independently of Cox-2. In this study, we investigated the effects of sulindac and its metabolite, sulindac sulfide on modulation of the critical survival kinase, protein kinase B (PKB). Here, we demonstrate for the first time that treatment with either sulindac or sulindac sulfide results in a decrease in PKB activity, and we provide compelling evidence that this occurs through two distinct mechanisms. Additionally, we report that overexpression of, and conditional activation of PKB attenuates the apoptotic effects of sulindac, but not for sulindac sulfide -the metabolic metabolite of sulindac. We also demonstrate that treatment with sulindac sulfide, but not sulindac, results in a very early robust activation of both caspase-8 and -9. Furthermore, we show that the apoptotic effects of sulindac sulfide can be reverted by both the caspase-8 and -9 inhibitors. Evidence is provided to indicate that PKB is targeted by robust caspase activation due to sulindac sulfide. Hence, further investigation into the mechanisms regulating conversion of sulindac to sulindac sulfide (or direct use of the latter compound), may enhance our ability to target cancers with enhanced signaling through the growth factor➝phosphatidylinositol 3-kinase pathway.

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Sulindac causes regression of rectal polyps in familial adenomatous polyposis

Cited by 620 publications

References 14 publications

A Phase Ib Study of the Effects of Black Raspberries on Rectal Polyps in Patients with Familial Adenomatous Polyposis

A Phase Ib Study of the Effects of Black Raspberries on Rectal Polyps in Patients with Familial Adenomatous Polyposis

Effect of aspirin on the Wnt/β-catenin pathway is mediated via protein phosphatase 2A

Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide

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