Clopidogrel in a combined therapy with anticancer drugs—effect on tumor growth, metastasis, and treatment toxicity: Studies in animal models

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.

Platelet Metabolism and Other Targeted Drugs; Potential Impact on Immunotherapy

“…The role of platelets in reducing cell death and enabling metastasis was also shown by activating YAP1 signaling in ovarian cancer ( 27 ). Similarly, many other reports show an active involvement of platelets in tumorigenesis and metastasis ( 28 – 32 ).…”

Retinol-Binding Protein 4 Accelerates Metastatic Spread and Increases Impairment of Blood Flow in Mouse Mammary Gland Tumors

“…Measurement of fluorescence of lungs dissected during autopsy was performed using the In Vivo MS FX Pro system with coregistration of fluorescence and X-ray. The obtained fluorescence images were analyzed using the Carestream MI SE software based on analyzed regions as described previously [56].…”

Impacts of Cancer on Platelet Production, Activation and Education and Mechanisms of Cancer-Associated Thrombosis

“…Some studies performed on cancer mouse models have demonstrated that the use P2Y12 inhibitors, such as ticagrelor or clopidogrel, reduced tumor growth and metastasis in vivo [ 159 , 160 ]. The use of clopidogrel in combination with chemotherapeutic drugs enhanced vascular permeability and drug delivery [ 161 ]. Other studies, however, showed no effect of clopidogrel alone on the tumor growth of three cancer types, including breast, colorectal and prostate cancer, or, even worse, a pro-tumoral effect of prasugrel [ 161 , 162 ].…”

“…The use of clopidogrel in combination with chemotherapeutic drugs enhanced vascular permeability and drug delivery [ 161 ]. Other studies, however, showed no effect of clopidogrel alone on the tumor growth of three cancer types, including breast, colorectal and prostate cancer, or, even worse, a pro-tumoral effect of prasugrel [ 161 , 162 ]. Altogether the results observed may depend on the model studied and the design of the study.…”