Aspirin blocks proliferation in colon cells by inducing a G 1 arrest and apoptosis through activation of the checkpoint kinase ATM

Luciani, M. Gloria; Campregher, Christoph; Gasché, Christoph

doi:10.1093/carcin/bgm101

Cited by 51 publications

(37 citation statements)

References 53 publications

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“…Waf1/Cip1 in an ataxia-telangiectasia-mutated kinase-dependent way, 81 or activating NFjB pathway. 82 APC/bcatenin pathway plays a pivotal role in the development of various cancers, especially colon cancer.…”

Section: Mechanisms Of Actionsmentioning

confidence: 99%

Combination regimen with statins and NSAIDs: A promising strategy for cancer chemoprevention

Xiao

Yang

2008

Intl Journal of Cancer

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Statins and nonsteroidal antiinflammatory drugs (NSAIDs) are commonly prescribed for lowering cholesterol and antiinflammation, respectively. Recently, their potential roles as cancer chemopreventive agents have been subject to intensive studies. Human trials have not provided conclusive results on the protective effects of statins against different cancers, while more convincing results have been observed for cancer preventive effects of NSAIDs, especially on colorectal cancer. A promising strategy to enhance the cancer preventive efficacy of statins and NSAIDs is to use them in combination, which may produce synergy and lower the dose required for each agent. This strategy is of particular interest for potential use of low doses of statins and NSAIDs on a long-term basis for cancer chemoprevention; increased risks for gastrointestinal and cardiovascular side effects associated with the use of NSAIDs have been observed in colorectal cancer chemopreventive trials. This article reviews the evidence for the cancer preventive actions of statins and NSAIDs, as well as their possible synergistic action and the mechanisms involved. ' 2008 Wiley-Liss, Inc.Key words: statins; NSAIDs; cancer chemoprevention While the mortality from major chronic diseases, such as cardiovascular and cerebrovascular diseases, has decreased substantially during the past half century in the United States, the mortality from cancer has just begun to show a slight decrease. Cancer has become the number one killer of both men and women under age 85 years in the United States.1 A promising approach to controlling cancer is to prevent it before malignant events have occurred.2 Cancer chemoprevention refers to the use of natural or synthetic substances to inhibit, retard or reverse the carcinogenesis.3 A wealth of evidence from preclinical studies have convincingly demonstrated the cancer preventive efficacy of various agents in different animal models. However, the data from observational, case-control, cohort studies, and randomized trials in humans have overall demonstrated mixed results. Statins and nonsteroidal antiinflammatory drugs (NSAIDs) have been reported to be potential cancer chemopreventive agents. This review focuses on an attractive approach of chemoprevention using the combination of statins and NSAIDs. Statin and cancer chemopreventionStatins are small-molecule inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which are widely used as cholesterol-lowering drugs. Besides their use in the treatment of lipid disorders, statins have showed anticarcinogenic activities in many in vitro and in vivo preclinical studies, and attracted much attention in exploring their roles in cancer chemoprevention. Several observational human studies reported potential protective effects of statin use against overall risk of cancer, 4-6 whereas other studies did not 7,8 (Table I). In a case-control study in Quebec, Canada, statin use was found to be associated with a 28% reduction in the risk of developing cancer (RR 5 0.72, 95% ...

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Section: Mechanisms Of Actionsmentioning

confidence: 99%

Combination regimen with statins and NSAIDs: A promising strategy for cancer chemoprevention

Xiao

Yang

2008

Intl Journal of Cancer

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“…An apparent discrepancy is that the concentrations required to exert these effects in cancer cells were significantly higher than that required to inhibit the activity of COX-1 or COX-2, suggesting the implications of other potential targets (12,13). Indeed, cell-based studies have demonstrated that aspirin inhibits cell proliferation, induces cell-cycle arrest and apoptosis in multiple cancer cell lines irrespective of COX-2 expression level (14)(15)(16)(17)(18). Aspirin can also sensitize cancer cell to TRAIL-induced apoptosis through a COX-2-independent mechanism (19).…”

Section: Introductionmentioning

confidence: 99%

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Dai

Yan

et al. 2017

Clinical Cancer Research

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Purpose: Recent epidemiological and clinical studies have suggested the benefit of aspirin for patients with cancer, which inspired increasing efforts to demonstrate the anticancer ability of aspirin and reveal the molecular mechanisms behind. Nevertheless, the anticancer activity and related mechanisms of aspirin remain largely unknown. This study aimed to confirm this observation, and more importantly, to investigate the potential target contributed to the anticancer of aspirin.Experimental Design: A homogeneous time-resolved fluorescence (HTRF) assay was used to examine the impact of aspirin on heparanase. Streptavidin pull-down, surface plasmon resonance (SPR) assay, and molecular docking were performed to identify heparanase as an aspirin-binding protein. Transwell, rat aortic rings, and chicken chorioallantoic membrane model were used to evaluate the antimetastasis and anti-angiogenesis effects of aspirin, and these phenotypes were tested in a B16F10 metastatic model, MDA-MB-231 metastatic model, and MDA-MB-435 xenograft model.Results: This study identified heparanase, an oncogenic extracellular matrix enzyme involved in cancer metastasis and angiogenesis, as a potential target of aspirin. We had discovered that aspirin directly binds to Glu225 region of heparanase and inhibits the enzymatic activity. Aspirin impeded tumor metastasis, angiogenesis, and growth in heparanase-dependent manner.Conclusions: In summary, this study has illustrated heparanase as a target of aspirin for the first time. It provides insights for a better understanding of the mechanisms of aspirin in anticancer effects, and offers a direction for the development of smallmolecule inhibitors of heparanase.

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“…Many studies have focused on aspirin and its ability to inhibit the invasion of a number of cancer cells, including breast, colon, oesophageal and lung cancer cells [17, 18]. Moreover, there is some evidence that the use of aspirin is inversely related to the risks of developing prostate cancer [19, 20], and aspirin also influences prostate cancer growth and metastasis by down-regulation of androgen receptor and prostate-specific antigen [21, 22]. However, the potential molecular mechanisms by which aspirin inhibits prostate cancer cell invasion have not been clearly elucidated.…”

Section: Introductionmentioning

confidence: 99%

Aspirin Inhibits IKK-β-mediated Prostate Cancer Cell Invasion by Targeting Matrix Metalloproteinase-9 and Urokinase-Type Plasminogen Activator

Shi

Zhang

Feng

et al. 2017

Cell Physiol Biochem

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Background/Aims: Aspirin has been demonstrated to possess potent chemopreventive and anticancer effects on prostate cancer. However, the more detailed molecular mechanisms of aspirin to suppress prostate cancer cell invasion have not been clearly elucidated. Methods: Transwell assays were performed to evaluate the effects of aspirin on cell invasion. Matrix metalloproteinases (MMPs) and serine proteinases activities in cell media were examined by gelatin zymography and ELISA. In addition, inhibitor of κB (IκB) kinase-β (IKK-β) phosphorylation and IKK-β kinase activity were measured to assess the effects of aspirin on IKK-β activation. Results: We found that aspirin suppressed the invasion and attachment in human prostate cancer cells. Aspirin treatment significantly resulted in reduction of matrix metalloproteinase-9 (MMP-9) and upregulation of tissue inhibitors of metalloproteinase-1 (TIMP-1) activity, which are the proteolytic enzymes contributing to the degradation of extracellular matrix and basement membrane in cell invasion and metastasis. Our data further showed that aspirin was able to inhibit both urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) expression in the cells. In addition, aspirin treatment caused a strong decrease in nuclear factor-kappa B (NF-κB) activation, inhibitor of κB (IκB)-α phosphorylation together with translocation of NF-κB p65 to nucleus and IκB kinase (IKK)- β activation. Moreover, the inhibitory effects of aspirin on cell invasion were reversed by IKK-β overexpression, while the IKK inhibitor sensitizes the anti-invasive effect of aspirin in prostate cancer cells. Conclusion: The present research concluded that aspirin suppressed prostate cancer cell invasion by reducing MMP-9 activity and uPA expression through decreasing of IKK-β-mediated NF-κB activation, indicating that the ability of aspirin to inhibit cell invasion might be useful in the chemoprevention of metastatic prostate cancer.

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Aspirin blocks proliferation in colon cells by inducing a G 1 arrest and apoptosis through activation of the checkpoint kinase ATM

Cited by 51 publications

References 53 publications

Combination regimen with statins and NSAIDs: A promising strategy for cancer chemoprevention

Combination regimen with statins and NSAIDs: A promising strategy for cancer chemoprevention

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Aspirin Inhibits IKK-β-mediated Prostate Cancer Cell Invasion by Targeting Matrix Metalloproteinase-9 and Urokinase-Type Plasminogen Activator

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