Aspirin Inhibits Colon Cancer Cell and Tumor Growth and Downregulates Specificity Protein (Sp) Transcription Factors

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Abstract

Acetylsalicylic acid (aspirin) is highly effective for treating colon cancer patients postdiagnosis; however, the mechanisms of action of aspirin in colon cancer are not well defined. Aspirin and its major metabolite sodium salicylate induced apoptosis and decreased colon cancer cell growth and the sodium salt of aspirin also inhibited tumor growth in an athymic nude mouse xenograft model. Colon cancer cell growth inhibition was accompanied by downregulation of Sp1, Sp3 and Sp4 proteins and decreased expression of Sp-regulated gene products including bcl-2, survivin, VEGF, VEGFR1, cyclin D1, c-MET and p65 (NFκB). Moreover, we also showed by RNA interference that β-catenin, an important target of aspirin in some studies, is an Sp-regulated gene. Aspirin induced nuclear caspase-dependent cleavage of Sp1, Sp3 and Sp4 proteins and this response was related to sequestration of zinc ions since addition of zinc sulfate blocked aspirin-mediated apoptosis and repression of Sp proteins. The results demonstrate an important underlying mechanism of action of aspirin as an anticancer agent and, based on the rapid metabolism of aspirin to salicylate in humans and the high salicylate/aspirin ratios in serum, it is likely that the anticancer activity of aspirin is also due to the salicylate metabolite.

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A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer.

Robert Sandler, Susan Halabi, John A. Baron … (2003)

Experimental studies in animals and observational studies in humans suggest that regular aspirin use may decrease the risk of colorectal adenomas, the precursors to most colorectal cancers. We conducted a randomized, double-blind trial to determine the effect of aspirin on the incidence of colorectal adenomas. We randomly assigned 635 patients with previous colorectal cancer to receive either 325 mg of aspirin per day or placebo. We determined the proportion of patients with adenomas, the number of recurrent adenomas, and the time to the development of adenoma between randomization and subsequent colonoscopic examinations. Relative risks were adjusted for age, sex, cancer stage, the number of colonoscopic examinations, and the time to a first colonoscopy. The study was terminated early by an independent data and safety monitoring board when statistically significant results were reported during a planned interim analysis. A total of 517 randomized patients had at least one colonoscopic examination a median of 12.8 months after randomization. One or more adenomas were found in 17 percent of patients in the aspirin group and 27 percent of patients in the placebo group (P=0.004). The mean (+/-SD) number of adenomas was lower in the aspirin group than the placebo group (0.30+/-0.87 vs. 0.49+/-0.99, P=0.003 by the Wilcoxon test). The adjusted relative risk of any recurrent adenoma in the aspirin group, as compared with the placebo group, was 0.65 (95 percent confidence interval, 0.46 to 0.91). The time to the detection of a first adenoma was longer in the aspirin group than in the placebo group (hazard ratio for the detection of a new polyp, 0.64; 95 percent confidence interval, 0.43 to 0.94; P=0.022). Daily use of aspirin is associated with a significant reduction in the incidence of colorectal adenomas in patients with previous colorectal cancer. Copyright 2003 Massachusetts Medical Society

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Aspirin intake and survival after breast cancer.

Ellen Hertzmark, Lisa Li, Yanfeng Chen … (2010)

Animal and in vitro studies suggest that aspirin may inhibit breast cancer metastasis. We studied whether aspirin use among women with breast cancer decreased their risk of death from breast cancer. This was a prospective observational study based on responses from 4,164 female registered nurses in the Nurses' Health Study who were diagnosed with stages I, II, or III breast cancer between 1976 and 2002 and were observed until death or June 2006, whichever came first. The main outcome was breast cancer mortality risk according to number of days per week of aspirin use (0, 1, 2 to 5, or 6 to 7 days) first assessed at least 12 months after diagnosis and updated. There were 341 breast cancer deaths. Aspirin use was associated with a decreased risk of breast cancer death. The adjusted relative risks (RRs) for 1, 2 to 5, and 6 to 7 days of aspirin use per week compared with no use were 1.07 (95% CI, 0.70 to 1.63), 0.29 (95% CI, 0.16 to 0.52), and 0.36 (95% CI, 0.24 to 0.54), respectively (test for linear trend, P < .001). This association did not differ appreciably by stage, menopausal status, body mass index, or estrogen receptor status. Results were similar for distant recurrence. The adjusted RRs were 0.91 (95% CI, 0.62 to 1.33), 0.40 (95% CI, 0.24 to 0.65), and 0.57 (95% CI, 0.39 to 0.82; test for trend, P = .03) for 1, 2 to 5, and 6 to 7 days of aspirin use, respectively. Among women living at least 1 year after a breast cancer diagnosis, aspirin use was associated with a decreased risk of distant recurrence and breast cancer death.

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Effect of aspirin and NSAIDs on risk and survival from colorectal cancer.

Farhat V N Din, Evropi Theodoratou, Susan Farrington … (2010)

Previous studies have shown that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) lower colorectal cancer (CRC) risk. However, the lowest effective NSAID dose, treatment duration, and effects on survival are not defined. In a large population-based case-control study, we have explored the relationship between NSAID dose and duration, CRC risk and overall CRC-specific survival. The relationship between NSAID use and CRC risk was examined in 2279 cases and 2907 controls. Subjects completed food-frequency and lifestyle questionnaires. NSAID categories were low-dose aspirin (75 mg), non-aspirin NSAIDs (NA-NSAIDs) and any NSAID. Users were defined as taking >4 tablets/week for >1 month. ORs were calculated by logistic regression models and adjusted for potential confounding factors. Effect of NSAID use on all-cause and CRC-specific mortality was estimated using Logrank tests and Cox's hazard models. In all, 354 cases (15.5%) were taking low-dose aspirin compared to 526 controls (18.1%). Low-dose aspirin use was associated with decreased CRC risk (OR 0.78 95% CI 0.65 to 0.92, p=0.004), evident after 1 year and increasing with duration of use (p(trend)=0.004). NA-NSAID and any NSAID use were also inversely associated with CRC. There was no demonstrable effect of NSAIDS on all-cause (HR 1.11, p=0.22, 0.94-1.33) or CRC-specific survival (HR 1.01, p=0.93, 0.83-1.23). This is the first study to demonstrate a protective effect against CRC associated with the lowest dose of aspirin (75 mg per day) after only 5 years use in the general population. NSAID use prior to CRC diagnosis does not influence survival from the disease.

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Author and article information

Contributors

Aamir Ahmad: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 26 October 2012

Volume: 7

Issue: 10

Electronic Location Identifier: e48208

Affiliations

[1 ]Department of Veterinary Physiology & Pharmacology, Texas A&M University, College Station, Texas, United States of America

[2 ]Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, United States of America

Wayne State University School of Medicine, United States of America

Author notes

* E-mail: ssafe@ 123456cvm.tamu.edu

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: SP SS. Performed the experiments: SP IJ GC VN SOL. Analyzed the data: SP IJ GC SOL. Contributed reagents/materials/analysis tools: SS. Wrote the paper: SP IJ GC SS.

Article

Publisher ID: PONE-D-12-23952

DOI: 10.1371/journal.pone.0048208

PMC ID: 3482208

PubMed ID: 23110215

SO-VID: e99691eb-e047-4f5c-9bd0-5f0ac65b2fe7

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 9 August 2012

Date accepted : 24 September 2012

Page count

Pages: 14

Funding

This research was supported by the National Institutes of Health (R01 CA136571) and Texas AgriLife Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Aspirin Inhibits Colon Cancer Cell and Tumor Growth and Downregulates Specificity Protein (Sp) Transcription Factors

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Most cited references 36

A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer.

Aspirin intake and survival after breast cancer.

Effect of aspirin and NSAIDs on risk and survival from colorectal cancer.

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