Colorectal Cancer and Nonsteroidal Anti-inflammatory Drugs

Smalley, Walter E.; DuBois, Raymond N.

doi:10.1016/s1054-3589(08)60067-8

Cited by 321 publications

(177 citation statements)

References 54 publications

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“…Aspirin, a non-steroidal anti-inflammatory agent, provides a beneficial effect in clinical situations including heart disease, rheumatoid arthritis and cancer (41)(42)(43). The mechanism by which this and other similar drugs mediate their effects is thought to involve the inhibition of Cox function (44,45).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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show abstract

“…Studies in rodents indicate that nonsteroidal anti-in¯ammatory drugs (NSAIDs), which inhibit both COX-1 and COX-2, reduce carcinogeninduced intestinal cancer (Reddy et al, 1993. Epidemiological studies also suggest that aspirin reduces the risk of colorectal (Smalley and DuBois, 1997) and breast cancers (Harris et al, 1996). Studies with COX-1 and COX-2 knockout mice have further illustrated the role of COXs in skin (Langenbach et al, 1999) and intestinal cancers (Oshima et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Role of cyclic AMP responsive element in the UVB induction of cyclooxygenase-2 transcription in human keratinocytes

et al. 2001

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It has been shown that UVB irradiation induces expression of COX-2 and up-regulation of COX-2 plays a functional role in UVB tumor promotion. In this study, we examined the cis-elements in the human COX-2 promoter that may be responsible for the UVB induction of COX-2. Analyses with the COX-2 promoter region revealed that the cyclic AMP responsive element near the TATA box was essential for both basal and UVB induced COX-2 expression. This was further supported by studies using a dominant negative mutant of CREB, which strongly inhibited the activity of COX-2 promoter. Electrophoretic mobility shift assays indicated that CREB and ATF-1 were the major proteins binding to the COX-2 CRE. CREB and ATF-1 were phosphorylated upon UVB treatment, and SB202190, a p38 MAPK inhibitor, decreased the phosphorylation of CREB/ATF-1 and suppressed COX-2 promoter activity. In contrast, treatment with forskolin, an activator of adenylyl cyclase, led to phosphorylation of CREB and ATF-1 and activation of COX-2 promoter. Finally, enhanced binding of phospho-CREB/ATF-1 to the COX-2 CRE was observed after UVB induction. Thus, one signaling pathway for UVB induction of human COX-2 involves activation of p38, subsequent phosphorylation of CREB/ATF-1, and activation of the COX-2 CRE through enhanced binding of phosphorylated CREB/ ATF-1. Oncogene (2001) 20, 5164 ± 5172.

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“…NSAIDs have been shown to suppress colorectal carcinogenesis in both animal models and humans (Smalley and DuBois, 1997). The NSAID sulindac has the ability to upregulate p21 WAF1/CIP1 expression in colon carcinoma cell lines (Goldberg et al, 1996).…”

mentioning

confidence: 99%

Both PPARγ and PPARδ influence sulindac sulfide-mediated p21WAF1/CIP1 upregulation in a human prostate epithelial cell line

2005

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Nonsteroidal anti-inflammatory drugs (NSAIDs) including sulindac sulfide are known to exert cancer chemopreventative activity in a range of cell lines. This activity has been shown to involve the upregulation of the cyclindependent kinase inhibitor p21 WAF1/CIP1 . It is also known that NSAIDs can act as peroxisome proliferator-activated receptor (PPAR) agonists and antagonists. In this study, we show that sulindac sulfide acts both as a PPARc agonist and a PPARd antagonist in an immortalized prostatic epithelial cell line (PNT1A). We utilized siRNA technology to show that PPARc is required for both growth inhibition and p21 WAF1/CIP1 upregulation in response to sulindac sulfide treatment in PNT1A cells. In addition, the overexpression of PPARd partially rescued these cells from growth inhibition and also dramatically inhibited sulindac sulfide-mediated p21 WAF1/CIP1 upregulation. Together these data identify a novel link between PPARc/ PPARd/p21 WAF1/CIP1 and the cancer chemo-preventative properties of NSAIDs.

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Colorectal Cancer and Nonsteroidal Anti-inflammatory Drugs

Cited by 321 publications

References 54 publications

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

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

Role of cyclic AMP responsive element in the UVB induction of cyclooxygenase-2 transcription in human keratinocytes

Both PPARγ and PPARδ influence sulindac sulfide-mediated p21WAF1/CIP1 upregulation in a human prostate epithelial cell line

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