Abstract
Clopidogrel, a thienopyridine derivative with antiplatelet activity, is widely prescribed for patients with cardiovascular diseases. In addition to antiplatelet activity, antiplatelet agents possess anticancer and antimetastatic properties. Contrary to this, results of some studies have suggested that the use of clopidogrel and other thienopyridines accelerates the progression of breast, colorectal, and prostate cancer. Therefore, in this study, we aimed to evaluate the efficacy of clopidogrel and various anticancer agents as a combined treatment using mouse models of breast, colorectal, and prostate cancer. Metastatic dissemination, selected parameters of platelet morphology and biochemistry, as well as angiogenesis were assessed. In addition, body weight, blood morphology, and biochemistry were evaluated to test toxicity of the studied compounds. According to the results, clopidogrel increased antitumor and/or antimetastatic activity of chemotherapeutics such as 5-fluorouracil, cyclophosphamide, and mitoxantrone, whereas it decreased the anticancer activity of doxorubicin, cisplatin, and tamoxifen. The mechanisms of such divergent activities may be based on the modulation of tumor vasculature via factors, such as transforming growth factor β1 released from platelets. Moreover, clopidogrel increased the toxicity of docetaxel and protected against mitoxantrone-induced toxicity, which may be due to the modulation of hepatic enzymes and protection of the vasculature, respectively. These results demonstrate that antiplatelet agents can be useful but also dangerous in anticancer treatment and therefore use of thienopyridines in patients undergoing chemotherapy should be carefully evaluated.
Highlights
In cancer, a number of interactions between the activated vascular endothelial cells, cancer cells, and platelets might cause an imbalance in hemostasis
Mice were humanely euthanized by cervical dislocation if their body weights dropped more than 20% of the original weight for two consecutive measurements, if more than 30% of the original weight remained for one measurement, if their tumor grew larger than 2000 mm3 or were necrotic, or if mice were in a state of prostration
As we have shown in this study, clopidogrel can increase anticancer and antimetastatic activity of some of the known anticancer drugs, such as 5-FU, CP, or MTX, whereas it can decrease the efficacy of the other anticancer drugs, such as DOX, CDDP, and TMX
Summary
A number of interactions between the activated vascular endothelial cells, cancer cells, and platelets might cause an imbalance in hemostasis. Platelets can be activated by cancer cells in a process called tumor cell-induced platelet aggregation (TCIP). Anticancer activity and toxicity of clopidogrel combined with anticancer drugs. Framework Program STRATEGMED (grant coordinated by JCET-UJ No STRATEGMED1/ 233226/11/NCBR/2015). The publication was supported by Wroclaw Center of Biotechnology within a Program of The Leading National Research Center (KNOW) for years 2014–2018. The funding bodies did not participate in the design of the study and collection, analysis, and interpretation of data or in writing the manuscript
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