Aspirin and Low-Dose Nitric Oxide-Donating Aspirin Increase Life Span in a Lynch Syndrome Mouse Model
ABSTRACT Nonsteroidal anti-inflammatory drugs (NSAID) appear to be effective cancer chemopreventives. Previous cellular studies showed that aspirin (acetylsalicylic acid: ASA) and nitric oxide-donating ASA (NO-ASA) suppressed microsatellite instability (MSI) in mismatch repair (MMR)-deficient cells linked to the common cancer predisposition syndrome hereditary nonpolyposis colorectal cancer or Lynch syndrome (LS/HNPCC), at doses 300- to 3,000-fold less than ASA. Using a mouse model that develops MMR-deficient intestinal tumors that appear pathologically identical to LS/HNPCC, we show that ASA (400 mg/kg) and low-dose NO-ASA (72 mg/kg) increased life span by 18% to 21%. We also note a trend where ASA treatment resulted in intestinal tumors with reduced high MSI (H-MSI) and increased low MSI (L-MSI) as defined by the Bethesda Criteria. Low-dose NO-ASA had a minimal effect on MSI status. In contrast to previous studies, high-dose NO-ASA (720/1,500 mg/kg) treatments increased tumor burden, decreased life span, and exacerbated MSI uniquely in the LS/HNPCC mouse model. These results suggest that MMR-deficient tissues/mice may be specifically sensitive to intrinsic pharmacokinetic features of this drug. It is likely that long-term treatment with ASA may represent a chemopreventive option for LS/HNPCC patients. Moreover, as low-dose NO-ASA shows equivalent life span increase at 10-fold lower doses than ASA, it may have the potential to significantly reduce the gastropathy associated with long-term ASA treatment.
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ABSTRACT: This review presents the evidence in support of the IGF-1/mTOR/S6K1 signaling as the primary factor contributing to aging and cellular senescence. Reviewed are also specific interactions between mTOR/S6K1 and ROS-DNA damage signaling pathways. Outlined are critical sites along these pathways, including autophagy, as targets for potential antiaging (gero-suppressive) and/or chemopreventive agents. Presented are applications of flow- and laser scanning- cytometry utilizing phospho-specific Abs, to monitor activation along these pathways in response to the reported antiaging drugs rapamycin, metformin, berberine, resveratrol, vitamin D3, 2-deoxyglucose, and acetylsalicylic acid. Specifically, effectiveness of these agents to attenuate the level of constitutive mTOR signaling was tested by cytometry and confirmed by Western blotting through measuring phosphorylation of the mTOR-downstream targets including ribosomal protein S6. The ratiometric analysis of phosphorylated to total protein along the mTOR pathway offers a useful parameter reporting the effects of gero-suppressive agents. In parallel, their ability to suppress the level of constitutive DNA damage signaling induced by endogenous ROS was measured. While the primary target of each of these agents may be different the data obtained on several human cancer cell lines, WI-38 fibroblasts and normal lymphocytes suggest common downstream mechanism in which the decline in mTOR/S6K1 signaling and translation rate is coupled with a reduction of oxidative phosphorylation and ROS that leads to decreased oxidative DNA damage. The combined assessment of constitutive γH2AX expression, mitochondrial activity (ROS, ΔΨm), and mTOR signaling provides an adequate gamut of cell responses to test effectiveness of gero-suppressive agents. Described is also an in vitro model of induction of cellular senescence by persistent replication stress, its quantitative analysis by laser scanning cytometry, and application to detect the property of the studied agents to attenuate the induction of senescence. Discussed is cytometric analysis of cell size and heterogeneity of size as a potential biomarker used to asses gero-suppressive agents and longevity. © 2014 International Society for Advancement of Cytometry.Cytometry Part A 05/2014; 85(5). DOI:10.1002/cyto.a.22452 · 3.07 Impact Factor
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ABSTRACT: The first DNA mismatch repair gene was identified in Escherichia coli nearly fifty years ago. Since then, five decades of basic biomedical research on this important repair pathway have led to an extensive understanding of its molecular mechanism. The significance of this work was clearly highlighted in the early 1990's when mutations in the human homologs of the mismatch repair genes were identified as responsible for Lynch syndrome (also known as hereditary non-polyposis colon cancer), the most common form of hereditary colorectal cancer. Basic science research on mismatch repair in lower organisms directly led researchers to the discovery of this link between defective mismatch repair and cancer and continues to guide clinical decisions today. The knowledge that disrupted mismatch repair function gives rise to the nucleotide-level form of genomic instability called microsatellite instability continues to be an important diagnostic tool for identifying Lynch syndrome patients as well as sporadic cancer patients who suffer from mismatch repair-defective cancers. Today, clinicians are using the information about mismatch repair molecular mechanism to guide decisions about cancer therapy as well to devise new therapies. In this review, we will examine what is known about the molecular function of the human mismatch repair pathway. We will highlight how this information is being used in cancer diagnosis and treatment. We will also discuss strategies being designed to target the 10-15% of colorectal, endometrial, ovarian and other cancers with defective mismatch repair.Current drug targets 01/2014; 15(1). DOI:10.2174/1389450114666140106100128 · 3.60 Impact Factor
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ABSTRACT: A number of genetic syndromes are known to convey a high risk of colorectal cancer. Current standards of medical practice for these patients involve genetic testing followed by screening and surgical procedures. Pharmaceutical therapies for any of these syndromes are limited in number and are generally not approved by any regulatory body for applications in these genetic groups. This review discusses advances in mechanistic understanding of the disease processes leading to the development of promising pharmaceutical therapies. Clinical trials of potential chemotherapeutic agents must focus on the reduction of disease-related events, including cancer and cancer-related mortality, in patients with genetic syndromes.06/2012; 1(3):225-240. DOI:10.2217/crc.12.22