Abstract
Long-term administration of acetylsalicylic acid (ASA) was effective in prevention of colorectal cancer, whereas the efficacy of this compound in other cancer types, including breast cancer, has been less convincingly documented. Indeed, the antimetastatic effect of low-dose ASA was observed only in the early intravascular phase of metastasis of breast cancer. In the present work, we characterized the effects of long-term treatment with ASA on the late phase of pulmonary metastasis in a mouse orthotopic 4T1 breast cancer model. Mice were treated with ASA at a dose of 12 mg·kg-1 of body weight daily starting one week prior to inoculation of 4T1 breast cancer cells, and the treatment was continued throughout progression of the disease. ASA administration decreased platelet TXB2 production in ex vivo assays but did not change thrombin-induced platelet reactivity. Although the number of metastases in the lungs remained unchanged in ASA-treated mice, infiltration of inflammatory cells was increased concomitantly with higher G-CSF and serotonin concentrations in the lungs. Pulmonary NO production was compromised compared to control 4T1 mice. ASA treatment also evoked an increase in platelet and granulocyte counts and decreased systemic NO bioavailability along with increased markers of systemic oxidant stress such as higher GSSG/lower GSH concentrations in RBC. Analysis of eicosanoids in stirred blood demonstrated that administration of ASA at a dose of 12 mg·kg-1 to cancer-bearing mice had an effect beyond inhibition of platelet COX-1, suggesting long-term treatment with low-dose aspirin is not a selective murine platelet COX-1/TXA2 pathway inhibitor in cancer-bearing mice. In summary, quite surprisingly, long-term treatment with low-dose ASA administered until the advanced phase of breast cancer in a murine orthotopic model of 4T1 breast cancer negatively affected the phenotype of the disease.
Highlights
Acetylsalicylic acid (ASA) has been intensively studied over the last few decades with respect to its anti-metastatic effects
To characterise the therapeutic efficacy of long-term treatment of ASA in breast cancer, we studied the effects of low-dose ASA (12 mg kg-1) on disease progression and metastasis in an orthotopic murine model of breast cancer when therapy was initiated seven days prior to inoculation of 4T1 breast cancer cells, and continued throughout the progression of the disease, until its advanced stage
Fifty mice were randomly divided into control non-ASA-treated (4T1 group, 25 mice) and mice treated with ASA (4T1+ASA, 25 mice) (acetylsalicylic acid (Sigma Aldrich, A5376) premixed with chow) at a dose of ~12 mg Aspirin affects late phase of mouse breast cancer per kg of body weight per 24 h that is equivalent to ~100 mg per 24 h in a 70 kg-human [1]
Summary
Acetylsalicylic acid (ASA) has been intensively studied over the last few decades with respect to its anti-metastatic effects. In case studies and metanalysis of randomized clinical trials (where effects of ASA were examined in entities not related to cancer), it was documented that ASA used at low anti-platelet dose reduced primary cancer and metastasis incidence [4,5,6,7], the effects were not confirmed in the elderly people [8]. While ASA consistently lowered the incidence of gastrointestinal cancers (i.e. colorectal) [4] and is recommended for primary prevention of colorectal cancer in adults older than 76 years [10], the evidence for the efficacy of ASA in breast cancer patients is less convincing, with some reports supporting the anti-metastatic activity [11], and others showing no evident reduction of both the risk [12, 13] and the number of deaths [6]. There is an on-going ADD-ASPIRIN Trial [14] devoted to the potential use of ASA as an agent inhibiting post-surgery metastasis in cancer (including breast) patients, that will provide an important re-evaluation of and the anti-metastatic effects of aspirin, but the results have not yet been published
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