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Old 11-05-2009, 12:17 PM   #1
Rich66
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Aspirin as anticancer agent

Aspirin Intake and Survival After Breast Cancer

JCO Early Release, published online ahead of print Feb 16 2010
Journal of Clinical Oncology, 10.1200/JCO.2009.22.7918

Michelle D. Holmes,* Wendy Y. Chen, Lisa Li, Ellen Hertzmark, Donna Spiegelman, and Susan E. Hankinson From the Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Departments of Epidemiology and Biostatistics, Harvard School of Public Health, Boston, MA.

* To whom correspondence should be addressed. E-mail: michelle.holmes@channing.harvard.edu


LINK

FULL TEXT

Purpose: 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.
Methods: 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.
Results: 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.
Conclusion: 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.



http://www.everydayhealth.com/public...ntion_20100218

Quote:
those who took it six to seven days a week had a 64 percent reduction in risk of death during the follow-up. For some reason, those who took aspirin two to five days a week had an even greater risk reduction, 71 percent, Holmes found.
Quote:
"While the results from this study are exciting, there are some important caveats," he said. Like Holmes, he noted that the findings do not prove cause and effect.
"As noted by the study authors, it is possible that survival results could have been influenced by women with recurrent breast cancer being advised to stop taking aspirin during chemotherapy, resulting in an overestimate of any benefit of aspirin use," Jacobs said.
Medpage article:
http://www.medpagetoday.com/Hematolo...stCancer/18489


Quote:
The risk reduction for distant metastasis in breast cancer survivors taking aspirin at least two days a week was a significant 43% to 60% in the analysis of the Nurses' Health Study data through 2006.
Quote:
Compared with women who never used aspirin, the multivariate adjusted relative risk of breast cancer death was:
  • Similar for past users (RR 0.88, 95% confidence interval 0.64 to 1.22)
  • Similar for those with current use one day a week (RR 1.07, 95% CI 0.70 to 1.63)
  • Significantly lower for current two to five days-a week use (RR 0.29, 95% CI 0.16 to 0.52)
  • Significantly lower for current use six or seven days a week (RR 0.36, 95% CI 0.24 to 0.54)
For distant recurrence risk, the results were much the same (P=0.03 for trend).
The multivariate adjusted metastasis risks compared with women who never used aspirin was not reduced significantly with past (RR 1.03) or current one day a week use (RR 0.91) but was with two to five (RR 0.40, 95% CI 0.24 to 0.65) and six to seven days a week use (RR 0.57, 95% CI 0.39 to 0.82).
For overall mortality, the results were just as good (P=0.004 for trend), with multivariate-adjusted risk reductions of 47% for two to five day a week use (RR 0.53, 95% CI 0.37 to 0.76) and 46% for daily or nearly daily use (RR 0.54, 95% CI 0.41 to 0.70).
Quote:
"The lack of association with acetaminophen suggests that the associations seen with aspirin and NSAIDs may represent biologically plausible effects and not just confounding by indication," Holmes and colleagues wrote in the JCO paper.
Quote:
Nor did the study have any information on aspirin dose, although most regular use was likely for heart disease prevention at the 81 mg/day level, they suggested.
Int J Oncol. 2009 Mar;34(3):597-608.
Aspirin inhibits camptothecin-induced p21CIP1 levels and potentiates apoptosis in human breast cancer cells.

Alfonso LF, Srivenugopal KS, Arumugam TV, Abbruscato TJ, Weidanz JA, Bhat GJ.
Department of Pharmaceutical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
The ability of aspirin to trigger apoptosis in cancer cells is well known and is consistent with the clinical and epidemiological evidence on its chemopreventive effects in curtailing epithelial cancers, including breast cancer. We hypothesized that the anticancer effects of aspirin may involve acetylation of the tumor suppressor protein p53, a known regulator of apoptosis. In the present study, we determined if aspirin at the physiologically achievable concentration of 100 microM acetylates p53 and modulates the expression of p21CIP1, a protein involved in cell cycle arrest, and Bax, a pro-apoptotic protein. Using MDA-MB-231 human breast cancer cells, we demonstrate that aspirin at 100 microM concentration markedly acetylated the p53 protein, which was primarily localized to the nucleus. Aspirin induced p21CIP1 protein levels in a transient fashion in contrast to the sustained induction of Bax. The induction of p21CIP1 protein levels began at 3 h and was maximal at 6-8 h; however, it decreased to control levels by 30 h. In contrast, the anticancer drug, camptothecin (CPT) induced a steady accumulation of p21CIP1 protein. Remarkably, when cells were co-treated with aspirin and CPT, p21CIP1 levels were drastically downregulated, and this phenomenon was observed in many cancer cell lines. Incubation of recombinant p21 with cytoplasmic extracts from aspirin-treated cells caused its degradation suggesting the involvement of proteases in the disappearance of p21CIP1. Consistent with this data, aspirin decreased the survival of CPT-treated cells and greatly increased the extent of apoptosis. Our observation that aspirin has the ability to inhibit p21CIP1 after its initial induction has important implications in chemotherapy, and suggests its potential use to increase the efficacy of anticancer agents.

PMID: 19212664 [PubMed - indexed for MEDLINE]


Two CPT analogues have been approved and are used in cancer chemotherapy[4] today, topotecan and irinotecan. [5][6]



1: Med Hypotheses. 2009 Aug 17. [Epub ahead of print] Links

Aspirin-associated iron loss as an anticancer mechanism.

Mascitelli L, Pezzetta F, Sullivan JL.
Medical Service, Comando Brigata Alpina "Julia", Udine, Italy.
A consensus view has emerged favoring an anticancer effect of long-term aspirin use. Aspirin-induced loss of stored iron from chronic gastrointestinal bleeding is proposed as a mechanism underlying this beneficial effect. In iron depletion, less iron may be available for carcinogenesis through free-radical mediated mechanisms and for promotion of tumor growth. Low-dose aspirin increases gastrointestinal losses of transfused radiolabeled autologous red cells. Observational studies report lower serum ferritin values with regular aspirin use. A protective effect of induced iron reduction against cancer mortality has been confirmed in a recent trial (FeAST) with subjects randomized to iron reduction or observation.reductions in the FeAST trial were within conventionally normal reference ranges and were quantitatively similar to ferritin reductions in observational studies in regular aspirin users. Delayed anticancer effects of aspirin are compatible with the proposed mechanism, as continual microbleeding has a gradual cumulative effect on stored iron.
PMID: 19692186 [PubMed - as supplied by publisher



Would it synergize with Metformin (often paired with Troglitazone) too?:

Int J Oncol. 2009 Oct;35(4):837-44.

Mol Carcinog. 2009 Nov 11. [Epub ahead of print]
The synergistic anticancer effect of troglitazone combined with aspirin causes cell cycle arrest and apoptosis in human lung cancer cells.

Yan KH, Yao CJ, Chang HY, Lai GM, Cheng AL, Chuang SE.
Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, ROC.
Troglitazone (TGZ) is a synthetic thiazolidinedione drug belonging to a group of potent peroxisome proliferator-activated receptor gamma (PPARgamma) agonists known to inhibit proliferation, alter cell cycle regulation, and induce apoptosis in various cancer cell types. TGZ is an oral anti-type II diabetes drug that can reverse insulin resistance. For more then 100 yr, aspirin, a nonselective cyclooxygenase (COX) inhibitor, has been successfully used as an anti-inflammatory drug. Recently, Aspirin (ASA) and some other nonsteroidal anti-inflammatory drugs (NSAIDs) have drawn much attention for their protective effects against colon cancer and cardiovascular disease; it has been observed that ASA's anti-tumor effect can be attributed to inhibition of cell cycle progression, induction of apoptosis, and inhibition of angiogenesis. In this report we demonstrate for the first time that, when administered in combination, TGZ and ASA can produce a strong synergistic effect in growth inhibition and G(1) arrest in lung cancer CL1-0 and A549 cells. Examination by colony formation assay revealed an even more profound synergy. In Western blot, combined TGZ and ASA also could downregulate Cdk2, E2F-1, cyclin B1, cyclin D3 protein, and the ratio of phospho-Rb/Rb. Importantly, apoptosis was synergistically induced by the combination treatment, as evidenced by caspase-3 activation and PARP cleavage. The involvement of PI3K/Akt inhibition and p27 upregulation, as well as hypophosphorylation of Rac1 at ser71, were demonstrated. Taken together, these results suggest that clinically achievable concentrations of TGZ and ASA used in combination may produce a strong anticancer synergy that warrants further investigation for its clinical applications. (c) 2009 Wiley-Liss, Inc.

PMID: 19908241 [PubMed - as supplied by publisher]

http://en.wikipedia.org/wiki/Troglitazone
Troglitazone is no longer available on US, UK or Japanese market but perhaps aspirin synergizes with other diabetes meds..like Metformin



Aspisol (brand name) contains aspirin 75 mg, glycine 37.5 mg.


Exp Oncol. 2008 Dec;30(4):289-94.
Aspisol inhibits tumor growth and induces apoptosis in breast cancer.

ASPISOL INHIBITS TUMOR GROWTH AND INDUCES APOPTOSIS IN BREAST CANCER





Zhu XG, Tao L, Mei ZR, Wu HP, Jiang ZW.
Department of Pharmacology, Pharmacy Department, Bengbu Medical College, Bengbu 233003, China.
Nonsteroidal anti-inflammatory drugs inhibit cell proliferation and induce apoptosis in various cancer cell lines, which is considered to be an important mechanism for their anti-tumor activity and cancer prevention. However, the molecular mechanisms through which these compounds induce apoptosis are not well understood. AIM: to determine the effects of nonselective cyclooxygenase-2 (COX-2) inhibitor, aspisol on breast cancer cells in vitro and in vivo. METHODS: The cytotoxic activity of aspisol was evaluated by MTT assay. The apoptosis index of cells was measured by flow cytometry. Immunohistochemical staining was used to detect expressions of COX-2 and caspase-3 in MDA-MB-231 cells. The expression of bcl-2 and bax was analyzed by Western blot analysis. The content of prostaglandin E2 (PGE2) in MDA-MB-231 cells was estimated by ELISA. In vivo apoptosis of the tumor cells was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). RESULTS: Our results showed that aspisol reduced viability of MDA-MB-231 cells in time- and dose- dependent fashions and induced apoptosis by increase of caspase-3 and bax expressions while decrease of COX-2 and bcl-2 expression in vitro. In addition, exposure to aspisol decreased the basal release of PGE2. In vivo, aspisol also inhibited the proliferation of breast cancer cells and induced their apoptosis. CONCLUSIONS: Our in vitro and in vivo data indicated that the antitumor effects of aspisol on breast cancer cells was probably mediated by the induction of apoptosis, and it could be linked to the downregulation of the COX-2 or bcl-2 expression and up-regulation of caspase-3 or bax expression.

PMID: 19112426 [PubMed - indexed for MEDLINE]










Biochem Pharmacol. 2009 Nov 15;78(10):1298-304. Epub 2009 Jul 2.
Nitro-aspirin inhibits MCF-7 breast cancer cell growth: effects on COX-2 expression and Wnt/beta-catenin/TCF-4 signaling.

Nath N, Vassell R, Chattopadhyay M, Kogan M, Kashfi K.
Department of Physiology and Pharmacology, City University of New York Medical School, 138th Street and Convent Avenue, New York, NY 10031, United States. nnath@nyit.edu
There is current evidence implicating the Wnt/beta-catenin/TCF pathway in breast cancer. We investigated the effect of para- and meta-positional isomers of nitric oxide-releasing aspirin (NO-ASA), and aspirin (ASA) on MCF-7 human breast cancer cell growth and beta-catenin/TCF signaling. The p- and m-NO-ASA isomers strongly inhibited cell growth and beta-catenin/TCF transcriptional activity compared to ASA; the IC50s for growth inhibition were 57+/-4, 193+/-10 and >5000microM, and for transcriptional inhibition they were 12+/-1.8, 75+/-6.5 and >5000microM for p-, m-NO-ASA and ASA, respectively. p-NO-ASA reduced the expression of Wnt/beta-catenin downstream target gene cyclin D1, and total cellular beta-catenin levels. COX-2 expression was induced by p-NO-ASA, protein kinase C inhibitors reversed this induction. p-NO-ASA blocked the cell cycle transition at S to G2/M phase. These studies suggest a targeted chemopreventive/chemotherapeutic potential for NO-ASA against breast cancer.

PMID: 19576865 [PubMed - indexed for MEDLINE]




The differential cell signaling effects of two positional isomers of the anticancer NO-donating aspirin.

Hua A, Mackenzie GG, Rigas B.
Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, New York 11794-5200, USA.

We studied the mechanism by which the para and meta positional isomers of nitric oxide-donating aspirin (NO-ASA) inhibit human colon cancer cell growth. These compounds are promising chemopreventive agents and represent a broader class of novel drugs. The two isomers differ drastically in their 24-h IC50s for cell growth, which are 12 microM for p-NO-ASA and 230 microM for m-NO-ASA. We examined their effects on cell signaling cascades, including predominantly the mitogen activated protein kinases (MAPKs). The principal differences between the two isomers were: a) p-NO-ASA exerts its effect earlier than m-NO-ASA; b) the predominant effect of m-NO-ASA is on ERK1/2 and Akt; whereas that of p-NO-ASA is on JNK1/2, while both activate p38, with p-NO-ASA showing a stronger and earlier effect; c) ATF-2 is more responsive to m-NO-ASA and c-Jun to p-NO-ASA; d) both isomers seem to have similar effects on AP-1 binding, the main difference between them being the timing of the effect; p-NO-ASA's effect is early and m-NO-ASA's is late; e) p-NO-ASA has an earlier and stronger effect on p21, while m-NO-ASA's effect occurs later and is weaker; and f) cell cycle changes follow the effect on p21 expression. Our findings underscore the role of positional isomerism in modulating the pharmacological effects of drugs and have potentially important implications for the further development of these chemoprevention agents.

PMID: 19724920 [PubMed - in process]


Acta Pharmacol Sin. 2009 Dec 7. [Epub ahead of print]
Aspirin inhibits proliferation of gemcitabine-resistant human pancreatic cancer cells and augments gemcitabine-induced cytotoxicity.

Ou YQ, Zhu WB, Li Y, Qiu PX, Huang YJ, Xie J, He SM, Zheng XK, Leng TD, Xu D, Yan GM.
Department of Pharmacology, Zhong-shan Medical College, Sun Yat-Sen University, Guangzhou 510089, China.
AbstractAim:To investigate whether aspirin is able to augment gemcitabine-induced cytotoxicity in human pancreatic cancer cells.Methods:Two gemcitabine-insensitive human pancreatic cancer cell lines, PANC-1 and Capan-1, were used. Cells were treated with either aspirin or gemcitabine alone or both of them. Cell growth and apoptosis were determined by MTT assay, Annexin V or Hoechest 33258 staining. Cell cycle distribution was examined by flow cytometry. Western blot with specific phosphorylated protein antibodies was used to detect the activation of protein kinase. RT-PCR and Western blot were applied to assess the transcription and protein level for cyclin D1 and Bcl-2.Results: Aspirin alone significantly inhibits the proliferation of PANC-1 cells by causing cell cycle arrest at G(1) phase. Aspirin potentiates the anti-survival effect of gemcitabine as well as its pro-apoptotic effect in PANC-1 cells, although aspirin per se does not trigger apoptosis. Aspirin inhibits GSK-3beta activation and suppresses the expression of its downstream gene products (cyclin D1 and Bcl-2), which are implicated in proliferation, survival and chemoresistance of pancreatic cancer. The effects of aspirin on Capan-1, were similar to that on PANC-1. Conclusion:
Our results suggest that aspirin inhibits the proliferation of gemcitabine-resistant pancreatic cancer cells and augments the antisurvival effect of gemcitabine, probably by suppressing the activity of GSK-3beta and its downstream gene products.

PMID: 19966835 [PubMed - as supplied by publisher]






Int J Oncol. 2009 Mar;34(3):597-608.
Aspirin inhibits camptothecin-induced p21CIP1 levels and potentiates apoptosis in human breast cancer cells.

Alfonso LF, Srivenugopal KS, Arumugam TV, Abbruscato TJ, Weidanz JA, Bhat GJ.
Department of Pharmaceutical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
The ability of aspirin to trigger apoptosis in cancer cells is well known and is consistent with the clinical and epidemiological evidence on its chemopreventive effects in curtailing epithelial cancers, including breast cancer. We hypothesized that the anticancer effects of aspirin may involve acetylation of the tumor suppressor protein p53, a known regulator of apoptosis. In the present study, we determined if aspirin at the physiologically achievable concentration of 100 microM acetylates p53 and modulates the expression of p21CIP1, a protein involved in cell cycle arrest, and Bax, a pro-apoptotic protein. Using MDA-MB-231 human breast cancer cells, we demonstrate that aspirin at 100 microM concentration markedly acetylated the p53 protein, which was primarily localized to the nucleus. Aspirin induced p21CIP1 protein levels in a transient fashion in contrast to the sustained induction of Bax. The induction of p21CIP1 protein levels began at 3 h and was maximal at 6-8 h; however, it decreased to control levels by 30 h. In contrast, the anticancer drug, camptothecin (CPT) induced a steady accumulation of p21CIP1 protein. Remarkably, when cells were co-treated with aspirin and CPT, p21CIP1 levels were drastically downregulated, and this phenomenon was observed in many cancer cell lines. Incubation of recombinant p21 with cytoplasmic extracts from aspirin-treated cells caused its degradation suggesting the involvement of proteases in the disappearance of p21CIP1. Consistent with this data, aspirin decreased the survival of CPT-treated cells and greatly increased the extent of apoptosis. Our observation that aspirin has the ability to inhibit p21CIP1 after its initial induction has important implications in chemotherapy, and suggests its potential use to increase the efficacy of anticancer agents.






Carcinogenesis. 2009 Mar;30(3):512-9. Epub 2009 Jan 9.
Phosphoaspirin (MDC-43), a novel benzyl ester of aspirin, inhibits the growth of human cancer cell lines more potently than aspirin: a redox-dependent effect.

Zhao W, Mackenzie GG, Murray OT, Zhang Z, Rigas B.
Department of Medicine, Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794-5200, USA.

FREE TEXT

Aspirin is chemopreventive against colon and probably other cancers, but this effect is relatively weak and its chronic administration to humans is associated with significant side effects. Because of these limitations, extensive effort has been exerted to improve the pharmacological properties of aspirin. We have determined the anticancer activity and mechanisms of action of the novel para positional isomer of phosphoaspirin [P-ASA; MDC-43; 4-((diethoxyphosphoryloxy)methyl)phenyl 2-acetoxybenzoate]. P-ASA inhibited the growth of 10 human cancer cell lines originating from colon, lung, liver, pancreas and breast, at least 18- to 144-fold more potently than conventional aspirin. P-ASA achieved this effect by modulating cell kinetics; compared with controls, P-ASA reduced cell proliferation by up to 68%, increased apoptosis 5.5-fold and blocked cell cycle progression in the G(2)/M phase. P-ASA increased intracellular levels of reactive oxygen species (ROS), depleted glutathione levels and modulated cell signaling predominantly through the mitogen-activated protein kinase (p38 and c-jun N-terminal kinase), cyclooxygenase (COX) and nuclear factor-kappa B pathways. P-ASA targeted the mitochondria, increasing mitochondrial superoxide anion levels; this effect on ROS led to collapsed mitochondrial membrane potential and triggered the intrinsic apoptotic pathway. The antioxidant N-acetyl cysteine abrogated the cell growth inhibitory and signaling effects of P-ASA, underscoring the centrality of ROS in its mechanism of action. Our results, establishing P-ASA as a potent inhibitor of the growth of several human cancer cell lines, suggest that it may possess broad anticancer properties. We conclude that the novel P-ASA is a promising anticancer agent, which merits further evaluation.

PMID: 19136474 [PubMed - indexed for MEDLINE]






J Cancer Res Clin Oncol. 2001 Nov;127(11):681-6.
Paradoxical effect of aspirin on the growth of C6 rat glioma and on time of development of ENU-induced tumors of the nervous system.

Arrieta O, Guevara P, Reyes S, Palencia G, Rivera E, Sotelo J.
Neuroimmunology Unit, Instituto Nacional de Neurologia y Neurocirugía and Instituto de Investigaciones Biomédicas, Mexico City, Mexico. ogar@servidor.unam.mx
PURPOSE: Administration of acetylsalicylic acid (ASA), an inhibitor of the synthesis of prostaglandins and thrombzoxanes, decreases the incidence of colorectal cancer and other neoplasms and inhibits in vitro some tumor growth. We studied the effect of various doses of ASA on the growth of C6 glioma implanted in rats as well as the effect of chronic administration of ASA on time of development and incidence of tumors of the central nervous system (CNS) induced by prenatal exposure to ethylnitrosourea (ENU). METHODS: In a controlled study, various doses of ASA, 12.5, 25, 50, 100, 200, 300, and 400 mg/kg per day, were administered to Wistar rats in whom a subcutaneous C6 glioma had been transplanted. Changes in tumor size, histologic characteristics, mitotic index, cell proliferation, and vascular density were studied. In a parallel experiment, we administered ASA (70 mg/kg per day) to rats who were prenatally exposed to ENU; treatment started on day 50 of age, and continued until the end of the experiment at day 400. The time of tumor development as well as incidence, localization, and histological diagnosis were compared with matched controls. RESULTS: A paradoxical effect of ASA administration was observed on the dynamics of cell proliferation of C6 glioma. When high ASA doses were administered (200 or 400 mg/kg per day), tumor volume, cell proliferation, vascular density, and mitotic index increased. In contrast, when low doses were administered (12.5 or 25 mg/kg per day) the tumor size diminished. In the second experiment, localization and incidence of CNS tumors induced by ENU were similar in animals treated with ASA and in controls; however, in rats treated with ASA the time of tumor development was shortened. CONCLUSIONS: The growth-promoting effects of high doses of ASA found in the present study in both transplanted and chemically-induced brain tumors, might be due to the blockage of autocrine inhibitory factors dependent on the cyclooxygenase pathway or by increased vascular permeability and blood supply to the tumor due to inhibition of platelet aggregation. In contrast, the inhibition of tumor growth obtained with low ASA doses in transplanted glioma might be due to different mechanisms such as the induction of apoptosis.

PMID: 11710598 [PubMed - indexed for MEDLINE]



Invest Ophthalmol Vis Sci. 2008 Sep;49(9):3909-13. Epub 2008 May 16.Differential suppression of vascular permeability and corneal angiogenesis by nonsteroidal anti-inflammatory drugs.

LINK




Pakneshan P, Birsner AE, Adini I, Becker CM, D'Amato RJ.
Departments of Surgery, Harvard Medical School, Children's Hospital Boston, Boston, Massachusetts, USA.
PURPOSE: Angiogenesis, the formation of new capillary blood vessels, is an essential biological process under physiological conditions, including embryonic development, reproduction, and wound repair. Under pathologic conditions, this process plays a critical role in a variety of diseases such as cancer, rheumatoid arthritis, atherosclerosis, endometriosis, diabetic retinopathy, and age-related macular degeneration. The purpose of this study was to examine the effects of cyclooxygenase inhibitors on basic fibroblast growth factor (bFGF)- and vascular endothelial growth factor (VEGF)-mediated ocular neovascularization and permeability. METHODS: A modified Miles vascular permeability assay was used to examine VEGF-induced vascular hyperpermeability, and the mouse corneal model of angiogenesis was used to compare the efficacy of systemic treatment with different nonsteroidal anti-inflammatory drugs (NSAIDs) on bFGF- and VEGF-induced angiogenesis. RESULTS: The authors demonstrated that systemic application of most NSAIDs, but not acetaminophen, blocked VEGF-induced permeability in mice. However, systemic treatment of mice with NSAIDs resulted in the differential inhibition of bFGF-induced (5%-57%) and VEGF-induced (3%-66%) corneal angiogenesis. The selective COX-2 inhibitors were more effective at suppressing bFGF-induced angiogenesis than VEGF-induced angiogenesis. CONCLUSIONS: Though most NSAIDS are effective at suppressing vascular leak, there exists a differential efficacy at suppressing the angiogenic response of specific cytokines such as bFGF and VEGF.

PMID: 18487370 [PubMed - indexed for MEDLINE]




Quote:
NSAIDs are drugs with anti-inflammatory, antipyretic, and analgesic effects classified by their selectivity in inhibiting COX-1 and COX-2, with varying specificity for one or the other. They have been shown to inhibit tumor growth, though different mechanisms have been proposed. In this study, we examined the effects of several COX inhibitors on bFGF- and VEGF-mediated angiogenesis in a model of growth factor–dependent corneal neovascularization and in an animal model of VEGF-induced permeability. We found that the extent of this suppressive effect in these models varies between different drugs. One of the NSAIDs tested was indomethacin, which is commonly used to reduce fever, pain, stiffness, and swelling. It works by inhibiting the production of prostaglandins known to cause these symptoms. Indomethacin can inhibit oxygen-induced retinopathy of prematurity in animals.43 Findings in newborns, however, have not always been consistent. Although indomethacin treatment reduced the incidence of patent ductus arteriosus in premature infants, it did not have a significant effect on the outcome of retinopathy of prematurity.44 45 Indomethacin is a methylated indole derivative and a member of the arylalkanoic acid family. It has two additional modes of action with clinical importance: it inhibits the motility of polymorphonuclear leukocytes, similar to colchicine, and it uncouples oxidative phosphorylation in cartilaginous or hepatic mitochondria similar to salicylates. Our data showed that indomethacin potently inhibits bFGF- and VEGF-induced angiogenesis in the cornea micropocket assay and strongly suppresses VEGF-induced hyperpermeability in the Miles assay.
The selective NSAIDs examined in this study were celecoxib (Celebrex; Pfizer, New York, NY) and rofecoxib (Vioxx; Merck, Whitehouse Station, NJ). Celecoxib is used in the clinic for patients with osteoarthritis, rheumatoid arthritis, acute pain, and menstrual pain and symptoms. It also reduces the number of colon and rectum polyps in patients with familial adenomatous polyposis. Unlike the traditional NSAIDs that inhibit COX-1 and COX-2, celecoxib and rofecoxib are inhibitors of COX-2 alone. Although they had less inhibitory effects on angiogenesis than indomethacin, celecoxib and rofecoxib blocked bFGF-induced angiogenesis significantly by an average of 43% and 44%. However, these treatments had little or no effect on VEGF-induced corneal angiogenesis (Table 2) . These data show that the selective inhibition of COX-2 suppresses bFGF-induced neovascularization more effectively than VEGF-induced neovascularization. In contrast, indomethacin and ketoprofen, which are nonselective COX-1 and COX-2 inhibitors, suppressed bFGF- and VEGF-induced angiogenesis significantly. Naproxen suppressed bFGF-induced angiogenesis slightly more effectively than VEGF-induced angiogenesis, but the difference was not significant. Ibuprofen and aspirin, which are also nonselective COX-1 and COX-2 inhibitors, effectively suppressed permeability in the Miles assay but did not have a strong effect on corneal angiogenesis in our model.
The permeability-inducing effect of VEGF is easily suppressed by NSAIDs. Additionally, most NSAIDs suppressed the angiogenesis-stimulating effect of bFGF. However, the selective inhibitors of COX-2 were only effective at suppressing bFGF-induced, not VEGF-induced, angiogenesis. We have previously shown that after implantation of a bFGF pellet in the cornea, some VEGF is produced locally by stromal cells and macrophages, contributing to the total neovascular response.29 In fact, the inhibition of VEGF with a soluble VEGF receptor can block up to 50% of the neovascularization induced by a bFGF pellet implanted in the cornea by neutralizing this locally produced VEGF. We have found that COX-2–selective inhibitors demonstrate a similar pattern, wherein these agents inhibited approximately 50% of the bFGF-induced angiogenesis but did not directly inhibit VEGF-induced angiogenesis when a VEGF pellet was implanted. Recent reports have shown that celecoxib can directly inhibit VEGF mRNA and protein expression in models of diabetic retinopathy46 and cancer.47 Thus, it is probable that the effects of celecoxib and rofecoxib on bFGF-induced corneal neovascularization result from inhibition of the local upregulation and production of VEGF after bFGF pellet implantation. Therefore, selective inhibitors of COX-2 would be best used clinically to treat angiogenic disorders early in the course of disease, before the upregulation and secretion of large amounts of VEGF. Once VEGF is present, selective COX-2 inhibitors would be less active in directly inhibiting VEGF-stimulated angiogenesis, though they would still block VEGF-induced permeability.
In conclusion, NSAIDs have differential effects on growth factor–induced angiogenesis and leakage. Knowledge of these differential effects will enable the selection of the most effective therapy with the least toxicity for the treatment of a particular pathologic process dependent on bFGF or VEGF.





J Biol Chem. 2010 Feb 9. [Epub ahead of print]
Gentisic acid, a compound associated with plant defense and a metabolite of aspirin, heads a new class of in vivo fibroblast growth factor inhibitors.

Fernandez IS, Cuevas P, Angulo J, Lopez-Navajas P, Canales-Mayordomo A, Gonzalez-Corrochano R, Lozano RM, Valverde S, Jimenez-Barbero J, Romero A, Gimenez-Gallego G.
Consejo Superior de Investigaciones Cientificas, Spain;
Fibroblast growth factors are key proteins in many intercellular signaling networks. They normally remain attached to the extracellular matrix, which confers them a considerable stability. The unrestrained accumulation of fibroblast growth factors in the extracellular milieu, either due to uncontrolled synthesis or enzymatic release, contributes to the pathology of many diseases. Consequently, the neutralization of improperly mobilized fibroblast growth factors is of clear therapeutic interest. In pursuing described rules to identify potential inhibitors of these proteins, gentisic acid, a plant pest-controlling compound, an aspirin and vegetarian diet common catabolite, and a component of many traditional liquors and herbal remedies, was singled out as a powerful inhibitor of fibroblast growth factors. Gentisic acid was used as a lead to identify additional compounds with better inhibitory characteristics generating a new chemical class of fibroblast growth factor inhibitors that includes the agent responsible for alkaptonuria. Through low and high resolution approaches, using representative members of the fibroblast growth factor family and their cell receptors, it was shown that this class of inhibitors may employ two different mechanism to interfere with the assembly of the signaling complexes that trigger fibroblast growth factor-driven mitogenesis. In addition, we obtained evidence from in vivo disease models that this group of inhibitors may be of interest to treat cancer and angiogenesis-dependent diseases.

PMID: 20145243 [PubMed - as supplied by publisher]



Anticancer Res. 2008 Jul-Aug;28(4B):2093-9.
Regulation of inflammation- and angiogenesis-related gene expression in breast cancer cells and co-cultured macrophages.

Burnett GT, Weathersby DC, Taylor TE, Bremner TA.
Department of Biology, Howard University, NW, Washington DC 20059, USA.
BACKGROUND: Tumor-associated macrophages (TAMs) secrete key modifiers of tumor progression and their modification has been proposed as a therapeutic strategy. Phenotypic changes that may render TAMs selectively vulnerable to anti-cancer agents were examined. MATERIALS AND METHODS: Gene arrays, reverse transcription-polymerase chain reaction and Western blotting were used to study inflammation- and angiogenesis-related gene expression in co-cultured breast cancer cells and macrophages and to determine how their interactions were affected by tamoxifen and aspirin. RESULTS: MCF-7 (mammary adenocarcinoma) cells down-regulated macrophage migration inhibitory factor (MIF), but tamoxifen-pretreated MCF-7 cells up-regulated MIF in co-cultured macrophages. Two molecular variants of MIF were observed in the co-cultured MCF-7 cells. Aspirin induced IL-10 expression in the macrophages, MCF-7 and tamoxifen-pretreated MCF-7 cells. Aspirin-pretreated macrophages potently induced IL-10 expression in the MCF-7 cells. CONCLUSION: Because MIF is a determinant of the M1 macrophage activation state, the MCF-7-induced ablation of MIF in TAMs is suggestive of partial M2 polarization. Tamoxifen modulates MCF-7 regulation of TAM gene expression and aspirin alters macrophage regulation of MCF-7 gene expression.

PMID: 18751381 [PubMed - indexed for MEDLINE]




Clin Cancer Res. 2008 May 15;14(10):3070-6.
Tamoxifen and aromatase inhibitors differentially affect vascular endothelial growth factor and endostatin levels in women with breast cancer.

Holmes CE, Huang JC, Pace TR, Howard AB, Muss HB.
Department of Medicine, University of Vermont, Burlington, Vermont, USA. ceholmes@uvm.edu
PURPOSE: Circulating and cellular proangiogenic and antiangiogenic proteins such as vascular endothelial growth factor (VEGF) and endostatin contribute to the local angiogenic balance. We explored the effects of tamoxifen and aromatase inhibitors on concentrations of VEGF and endostatin in plasma, serum, and platelet releasate (induced by platelet activation). EXPERIMENTAL DESIGN: VEGF and endostatin concentrations were measured with a quantitative immunoassay before and after 1 to 5 weeks of treatment in 30 women with breast cancer treated with either tamoxifen (n = 14) or aromatase inhibitors (n = 16). Platelet activation was induced by a thrombin receptor agonist. RESULTS: Tamoxifen therapy resulted in an increase in platelet releasate concentrations of VEGF (P = 0.01) but no change in plasma VEGF. In contrast, aromatase inhibitor therapy did not affect serum, plasma, or platelet releasate VEGF. In univariate analysis, aspirin use attenuated the tamoxifen-associated increase in VEGF in the platelet releasate and decreased serum levels of VEGF (P = 0.03). Aromatase inhibitor therapy resulted in a decrease in serum endostatin concentrations (P = 0.04), whereas plasma concentrations of endostatin tended to be higher during treatment with aromatase inhibitors (P = 0.06). Tamoxifen therapy resulted in no change in serum or plasma endostatin concentrations. Platelet releasate concentrations of endostatin did not change with either treatment. Interindividual variability was noted among both aromatase inhibitor--and tamoxifen-treated patients. CONCLUSIONS: Tamoxifen and aromatase inhibitor therapy affect VEGF and endostatin levels and likely contribute to the angiogenic balance in breast cancer patients. Aspirin decreased the proangiogenic effects of tamoxifen, suggesting that antiplatelet and/or antiangiogenic therapy might improve the effectiveness of tamoxifen in women with breast cancer.

PMID: 18483373 [PubMed - indexed for MEDLINE]



Cancer Sci. 2010 Jun 25. [Epub ahead of print]
Acetyl salicyclic acid (aspirin) improves synthesis of maspin and lowers incidence of metastasis in breast cancer patients.

Bhattacharyya M, Girish GV, Ghosh R, Chakraborty S, Sinha AK.
Sinha Institute of Medical Science and Technology, Garia, Calcutta, India.
Abstract

Maspin, a 42 kDa protein produced in normal breast cells, has been shown to inhibit the invasion and metastasis of breast cancer in an animal model. Ingestion of acetylsalicylic acid (aspirin) by breast cancer patients has been reported to restore the systemic synthesis of maspin through the stimulation of systemic nitric oxide production. Studies were carried out to determine the effect of aspirin on the incidence of breast cancer metastasis, which is reported to occur in 50% of patients who have previously received chemotherapy, radiation, and/or surgery. Thirty-five female patients (aged 41-65 years) with breast cancer who had previously received these therapies took one 75 mg/70 kg body weight enteric-coated aspirin tablet every 24 h, after an adequate meal, for 3 years. Their plasma nitric oxide and maspin levels were measured. The occurrence of metastasis was ascertained monthly by a qualified oncologist, and confirmed, if necessary, by biopsy. Daily ingestion of aspirin by participants resulted in an increase in maspin levels from 0.95 +/- 0.04 to 4.63 +/- 0.05 nM after 24 h. These levels were maintained for 3 years. These studies suggest that daily ingestion of aspirin might significantly reduce the incidence of breast cancer metastasis in patients who have previously received anticancer therapies. (Cancer Sci 2010).

PMID: 20670296 [PubMed - as supplied by publisher]



Int J Clin Pract. 2008 Mar;62(3):444-9. Epub 2008 Jan 8.
NSAIDs and breast cancer: a possible prevention and treatment strategy.

Agrawal A, Fentiman IS.
Hedley Atkins Breast Unit, Guy's Hospital, London, UK.
Abstract

CONTEXT: Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) and thereby reduce prostaglandin synthesis. Abnormally upregulated COX and prostaglandins are features of breast cancer so NSAIDs might have a role in treatment and prevention of the disease. OBJECTIVE: To review the available epidemiological data on the relation between NSAIDs and risk of breast cancer together with interventional studies in established disease. RESULTS: Both case-control and cohort studies indicate a moderate reduction in risk of breast cancer among women taking NSAID particularly aspirin. There may be a reduction in oestrogen receptor positive tumours in aspirin users but results are heterogeneous. It is not possible to estimate the dose-response effect for duration of use. In patients with breast cancer, aspirin increased levels of serum nitric oxide (NO) and maspin both of which inhibit growth of breast cancer cells in vitro. Furthermore, a reduced breast cancer and all-cause mortality has been reported in those taking NSAIDs after diagnosis. The cyclooxygenase 2 (COX-2) inhibitor celecoxib showed promising preliminary efficacy and acceptability in combination with exemestane in advanced breast cancer although cardiotoxicity led to discontinuation of celecoxib in a prevention trial for individuals with colonic polyps. CONCLUSIONS: NSAIDs may reduce breast cancer risk by 20% but the optimal type, dose and duration is still undetermined together with the feasibility of such an intervention in an at risk population. There may be a role for NSAIDs in combination with endocrine therapies as either an adjuvant or palliative treatment for women with established breast cancer.

PMID: 18194278 [PubMed - indexed for MEDLINE]
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