Celecoxib Downregulates CD133 Expression Through Inhibition of the Wnt Signaling Pathway in Colon Cancer Cells

Deng, Yanhong; Su, Qiao; Mo, Jianwen; Fu, Xinhui; Zhang, Yan; Lin, Edward H.

doi:10.3109/07357907.2012.754458

Cited by 35 publications

(32 citation statements)

References 12 publications

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“…This is consistent with a recent study that celecoxib inhibits tumor sphere through CD133 downregulation in colon cancer [28]. Importantly, the anti-CSCs function of celecoxib could not be reversed by exogenous PGE 2 supply, implicating COX-2/PGE 2 -independent pathway might be involved in celecoxib-induced stemness suppression.…”

Section: Discussionsupporting

confidence: 92%

Celecoxib suppresses hepatoma stemness and progression by up-regulating PTEN

et al. 2013

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Celecoxib, a COX-2 inhibitor and non-steroidal anti-inflammatory drug, can prevent several types of cancer, including hepatocellular carcinoma (HCC). Here we show that celecoxib suppressed the self-renewal and drug-pumping functions in HCC cells. Besides, celecoxib depleted CD44 + /CD133 + hepatic cancer stem cells (hCSC). Prostaglandin E2 (PGE2) and CD133 overexpression did not reverse the celecoxib-induced depletion of hCSC. Also, celecoxib inhibited progression of rat Novikoff hepatoma. Moreover, a 60-day celecoxib program increased the survival rate of rats with hepatoma. Histological analysis revealed that celecoxib therapy reduced the abundance of CD44 + /CD133 + hCSCs in hepatoma tissues. Besides, the hCSCs depletion was associated with elevated apoptosis and blunted proliferation and angiogenesis in hepatoma. Celecoxib therapy activated peroxisome proliferator-activated receptor γ (PPARγ) and up-regulated PTEN, thereby inhibiting Akt and disrupting hCSC expansion. PTEN gene delivery by adenovirus reduced CD44/CD133 expression in vitro and hepatoma formation in vivo. This study suggests that celecoxib suppresses cancer stemness and progression of HCC via activation of PPARγ/PTEN signaling.

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Section: Discussionsupporting

confidence: 92%

Celecoxib suppresses hepatoma stemness and progression by up-regulating PTEN

et al. 2013

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“…COX-2 inhibitors may target the Wnt pathway by inhibiting prostaglandin E2 (PGE 2 ), the product of COX-2, which acts to phosphorylate GSK-3 (Figure 1 [Fujino et al, 2002]). Celecoxib, a NSAID and a COX-2 inhibitor, has been shown to decrease CD133 expression, a surface marker of prostate CSCs, by targeting the Wnt pathway, and this effect was observed to be independent of its COX-2 inhibiting activity (Deng et al, 2013). In order to circumvent the toxicities associated with long term COX-2 inhibition, one group suggests using synthetic derivatives of sulindac, another NSAID that was previously mentioned, that do not target COX-2 and were successful in limiting colon cancer cell growth and promoting apoptosis in vitro (Li et al, 2013; Whitt et al, 2012).…”

Section: Targeting the Wnt Pathwaymentioning

confidence: 99%

Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28

McDermott

Jimeno

2015

Pharmacology & Therapeutics

214

167

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The Wnt signaling pathways are a group of signal transduction pathways that play an important role in cell fate specification, cell proliferation and cell migration. Aberrant signaling in these pathways has been implicated in the development and progression of multiple cancers by allowing increased proliferation, angiogenesis, survival and metastasis. Activation of the Wnt pathway also contributes to the tumorigenicity of cancer stem cells (CSCs). Therefore, inhibiting this pathway has been a recent focus for cancer research with multiple targetable candidates in development. OMP-54F28 is a fusion protein that combines the cysteine-rich domain of frizzled family receptor 8 (Fzd8) with the immunoglobulin Fc domain that competes with the native Fzd8 receptor for its ligands and antagonizes Wnt signaling. Preclinical models with OMP-54F28 have shown reduced tumor growth and decreased CSC frequency as a single agent and in combination with other chemotherapeutic agents. Due to these findings, a phase 1a study is nearing completion with OMP-54F28 in advanced solid tumors and 3 phase 1b studies have been opened with OMP-54F28 in combination with standard of care chemotherapy backbones in ovarian, pancreatic and hepatocellular cancers. This article will review the Wnt signaling pathway, preclinical data on OMP-54F28 and other Wnt pathway inhibitors and ongoing clinical trials.

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“…Significantly, the resistance of these cells to conventional chemotherapeutic regimes suggests that CSCs play a major role in drug resistance and treatment failure [22]. Interestingly, COX-2 has been shown to be upregulated in colon [23] and breast CSCs and constituted part of an eight-gene signature that correlated with breast cancer patient survival [24]. …”

Section: Introductionmentioning

confidence: 99%

The long-acting COX-2 inhibitor mavacoxib (Trocoxil™) has anti-proliferative and pro-apoptotic effects on canine cancer cell lines and cancer stem cells in vitro

et al. 2014

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BackgroundThe NSAID mavacoxib (Trocoxcil™) is a recently described selective COX-2 inhibitor used for the management of inflammatory disease in dogs. It has a long plasma half-life, requiring less frequent dosing and supporting increased owner compliance in treating their dogs. Although the use of NSAIDs has been described in cancer treatment in dogs, there are no studies to date that have examined the utility of mavacoxib specifically.ResultsIn this study we compared the in vitro activity of a short-acting non-selective COX inhibitor (carprofen) with mavacoxib, on cancer cell and cancer stem cell survival. We demonstrate that mavacoxib has a direct cell killing effect on cancer cells, increases apoptosis in cancer cells in a manner that may be independent of caspase activity, and has an inhibitory effect on cell migration. Importantly, we demonstrate that cancer stem cells derived from osteosarcoma cell lines are sensitive to the cytotoxic effect of mavacoxib.ConclusionsBoth NSAIDs can inhibit cancer cell proliferation and induce apoptosis in vitro. Importantly, cancer stem cells derived from an osteosarcoma cell line are sensitive to the cytotoxic effect of mavacoxib. Our results suggest that mavacoxib has anti-tumour effects and that this in vitro anti-cancer activity warrants further study.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-014-0184-9) contains supplementary material, which is available to authorized users.

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Celecoxib Downregulates CD133 Expression Through Inhibition of the Wnt Signaling Pathway in Colon Cancer Cells

Cited by 35 publications

References 12 publications

Celecoxib suppresses hepatoma stemness and progression by up-regulating PTEN

Celecoxib suppresses hepatoma stemness and progression by up-regulating PTEN

Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28

The long-acting COX-2 inhibitor mavacoxib (Trocoxil™) has anti-proliferative and pro-apoptotic effects on canine cancer cell lines and cancer stem cells in vitro

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