Tamoxifen Directly Inhibits Platelet Angiogenic Potential and Platelet-Mediated Metastasis

Abstract

Objective Platelets, which are mainly known for their role in hemostasis, are now known to play a crucial role in metastasis. Tamoxifen is a selective estrogen receptor modulator that is widely used for the treatment of breast cancer. Tamoxifen and its metabolites have been shown to directly impact platelet function suggesting that this drug has additional mechanisms of action. The purpose of this study was to determine whether tamoxifen exerts anti-tumor effects through direct platelet inhibition. Approach and Results This study found that pretreatment with tamoxifen leads to a significant inhibition of platelet activation. Platelets exposed to tamoxifen released significantly lower amounts of pro-angiogenic regulator VEGF. In vitro angiogenesis assays confirmed that tamoxifen pretreatment led to diminished capillary tube formation and decreased endothelial migration. Tamoxifen and its metabolite, 4-Hydroxytamoxifen, also significantly inhibited the ability of platelets to promote metastasis in vitro. Using a membrane based array, we identified several proteins associated with angiogenesis metastasis that were lower in activated releasate from tamoxifen treated platelets including angiogenin, CXCL1, CCL5, EGF, CXCL5 and PDGF-BB while anti-angiogenic angiopoietin-1 was elevated. Platelets isolated from patients on tamoxifen maintenance therapy were also found to have decreased activation responses, diminished VEGF release and lower angiogenic and metastatic potential. Conclusions We demonstrate that tamoxifen and its metabolite 4-Hydroxytamoxifen directly alters platelet function leading to decreased angiogenic and metastatic potential. Furthermore, this study supports the idea of utilizing targeted platelet therapies to inhibit the platelet’s role in angiogenesis and malignancy.

Platelet-derived Extracellular Vesicles: An Emerging Therapeutic Approach

“…However, aspirin has several side effects including increased risk of bleeding, heavy menses, increased nausea and vomiting 74 . Although tamoxifen was found to be more focused on angiogenesis and malignancy 75 , newly-designed drugs aimed at inhibiting the release of P-EVs caused by cancer cells, rather than the entire function of platelets, could have the prospect of broad application, because of the specific targeting of P-EVs related to tumor metastasis and the avoidance of influence on the coagulation function which results in several side effects. In addition, gene therapy to inhibit the uptake ability of P-EVs in cancer cells or the production and release ability of T-EVs which could recruit or regulate platelets, or immunotherapy targeting T-EVs to eliminate T-EVs in the blood circulation system, could also be potential future therapeutic approaches for the prevention of tumor metastasis.…”

Widely disseminated metastatic Ewing sarcoma: Sustained, complete metabolic response to first‐line oral metronomic chemotherapy

“…He was started on an OMCT protocol consisting of cyclophosphamide (Cy), etoposide (Eto) both at 50 mg/m 2 once daily dose (capping at 50 mg) for 21 days and tamoxifen (20 mg/m 2 with cap at 20 mg twice daily) repeated every 28 days. In addition to the antiestrogenic action, tamoxifen has antiangiogenic action ,mediated by several mechanisms, vascular endothelial growth factor among them 14‐16 . Hence, it is used as part of the OMCT protocol for ES in our institute 10,11 .…”

Precautions for Patients Taking Tamoxifen

“…Tamoxifen plasma levels decline with an elimination half-life of 7 to 14 days (Hussain & Kneeshaw, 2012). Additionally, tamoxifen and its metabolite, 4-hydroxytamoxifen, significantly inhibited the ability of platelet aggregation (Johnson et al, 2017). In certain surgical situations, tamoxifen may be held to prevent such complications.…”