Targeting Platelets for the Treatment of Cancer

Elaskalani, Omar; Berndt, Michael C.; Falasca, Marco; Metharom, Pat

doi:10.3390/cancers9070094

Cited by 59 publications

(54 citation statements)

References 179 publications

(207 reference statements)

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“…As shown in Figure 7 and Figure S3B, this treatment combination significantly reduced tumour growth, indicating that ticagrelor's effect on tumour growth was not affected by a fully developed immune system. Importantly, the addition of ticagrelor to gemcitabine did not produce any noted adverse effects as the final weights and the haematological parameters were similar between the gemcitabine and combined therapy groups [42].…”

Section: The Combination Of Ticagrelor and Gemcitabine Significantly mentioning

confidence: 88%

“…Targeting ATP receptors in cancer cells or the ADP receptor P2Y12 in platelets have attracted overwhelming interest from cancer researchers recently [13,16]. However, the role of ADP and P2Y12 in cancer cells remains poorly investigated.…”

Section: Discussionmentioning

confidence: 99%

“…P2Y12 is a target for several clinically available antithrombotic drugs [15]. Inhibition of platelet P2Y12 has been shown to reduce cancer growth and metastasis in ovarian, melanoma and lung cancer mice models [14,16]. However, the expression and signalling of P2Y12 in cancer cells are poorly investigated.…”

Section: Introductionmentioning

confidence: 99%

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Antiplatelet Drug Ticagrelor Enhances Chemotherapeutic Efficacy by Targeting the Novel P2Y12-AKT Pathway in Pancreatic Cancer Cells

Elaskalani

Domenichini

Razak

et al. 2020

Cancers

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Background: Extensive research has reported that extracellular ADP in the tumour microenvironment can stimulate platelets through interaction with the platelet receptor P2Y12. In turn, activated platelets release biological factors supporting cancer progression. Experimental data suggest that the tumour microenvironment components, of which platelets are integral, can promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Thus, overcoming chemoresistance requires combining multiple inhibitors that simultaneously target intrinsic pathways in cancer cells and extrinsic factors related to the tumour microenvironment. We aimed to determine whether ticagrelor, an inhibitor of the ADP–P2Y12 axis and a well-known antiplatelet drug, could be a therapeutic option for PDAC. Methods: We investigated a functional P2Y12 receptor and its downstream signalling in a panel of PDAC cell lines and non-cancer pancreatic cells termed hTERT-HPNE. We tested the synergistic effect of ticagrelor, a P2Y12 inhibitor, in combination with chemotherapeutic drugs (gemcitabine, paclitaxel and cisplatin), in vitro and in vivo. Results: Knockdown studies revealed that P2Y12 contributed to epidermal growth factor receptor (EGFR) activation and the expression of SLUG and ZEB1, which are transcriptional factors implicated in metastasis and chemoresistance. Studies using genetic and pharmacological inhibitors showed that the P2Y12–EGFR crosstalk enhanced cancer cell proliferation. Inhibition of P2Y12 signalling significantly reduced EGF-dependent AKT activation and promoted the anticancer activity of anti-EGFR treatment. Importantly, ticagrelor significantly decreased the proliferative capacity of cancer but not normal pancreatic cells. In vitro, synergism was observed when ticagrelor was combined with several chemodrugs. In vivo, a combination of ticagrelor with gemcitabine significantly reduced tumour growth, whereas gemcitabine or ticagrelor alone had a minimal effect. Conclusions: These findings uncover a novel effect and mechanism of action of the antiplatelet drug ticagrelor in PDAC cells and suggest a multi-functional role for ADP-P2Y12 signalling in the tumour microenvironment.

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Section: The Combination Of Ticagrelor and Gemcitabine Significantly mentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Antiplatelet Drug Ticagrelor Enhances Chemotherapeutic Efficacy by Targeting the Novel P2Y12-AKT Pathway in Pancreatic Cancer Cells

Elaskalani

Domenichini

Razak

et al. 2020

Cancers

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“…Another potential strategy to suppress platelet activation is to target ADP-mediated platelet activation with inhibitors of the P2Y12 receptor, such as clopidogrel. Several studies indicate that such therapeutic approaches, alone or in combination with aspirin, could be effective to treat cancer (76).…”

Section: Activated Platelets As Therapeutic Targets To Treat Cancermentioning

confidence: 99%

The pro-inflammatory role of platelets in cancer

Olsson

Cedervall

2018

Platelets

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Thrombosis is a frequent issue in cancer patients. Tumor-induced platelet activation and coagulation does not only constitute a significant risk for thrombosis, but also contribute to tumor progression by promoting critical processes such as angiogenesis and metastasis. In addition to their role in hemostasis, platelets are increasingly recognized as regulators of inflammation. By modulating the immune system, platelets regulate several aspects of cancer-associated pathology. Platelets influence the inflammatory response in cancer by affecting the activation status of the endothelium and by recruiting leukocytes to primary and metastatic tumor sites, as well as to distant organs unaffected by tumor growth. Furthermore, platelets participate in the formation of neutrophil extracellular traps, which can promote metastasis, thrombosis, and contribute to organ failure. In this review, we discuss the role of platelets as coordinators of the immune system during malignant disease and the potential of targeting platelets to prevent cancer-associated pathology.

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“…Platelets also interact with bacteria and other pathogens via GPIbα, GPVI, αIIbβ3, and other mechanisms [ 34 , 35 , 36 ]. In addition to pro-inflammatory cytokines, activated platelets also release growth factors and microparticles which could all potentially play an important role in cancer, albeit the association between abnormal platelet function related to bleeding or thrombotic/coagulopathy risk, immunosuppression and cancer survival, growth and/or metastasis is complex [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. Platelets may interact with metastatic cancer cells entering the blood stream via receptor-mediated adhesion and/or release of soluble factors, contribute to suppression of immune response towards cancer cells [ 52 ], and/or regulate localization within the microvasculature to enable redistribution and enhance survival.…”

Section: Platelet Function and Key Receptors Including Roles In Cmentioning

confidence: 99%

Bone Marrow Defects and Platelet Function: A Focus on MDS and CLL

Luu

Gardiner

Andrews

2018

Cancers

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The bloodstream typically contains >500 billion anucleate circulating platelets, derived from megakaryocytes in the bone marrow. This review will focus on two interesting aspects of bone marrow dysfunction and how this impacts on the quality of circulating platelets. In this regard, although megakaryocytes are from the myeloid lineage leading to granulocytes (including neutrophils), erythrocytes, and megakaryocytes/platelets, recent evidence has shown that defects in the lymphoid lineage leading to B cells, T cells, and natural killer (NK) cells also result in abnormal circulating platelets. Current evidence is limited regarding whether this latter phenomenon might potentially arise from (a) some form of as-yet-undetected defect common to both lineages; (b) adverse interactions occurring between cells of different lineages within the bone marrow environment; and/or (c) unknown disease-related factor(s) affecting circulating platelet receptor expression/function after their release from megakaryocytes. Understanding the mechanisms underlying how both myeloid and lymphoid lineage bone marrow defects lead to dysfunction of circulating platelets is significant because of the potential diagnostic and predictive value of peripheral platelet analysis for bone marrow disease progression, the additional potential effects of new anti-cancer drugs on platelet function, and the critical role platelets play in regulation of bleeding risk, inflammation, and innate immunity.

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Targeting Platelets for the Treatment of Cancer

Cited by 59 publications

References 179 publications

Antiplatelet Drug Ticagrelor Enhances Chemotherapeutic Efficacy by Targeting the Novel P2Y12-AKT Pathway in Pancreatic Cancer Cells

Antiplatelet Drug Ticagrelor Enhances Chemotherapeutic Efficacy by Targeting the Novel P2Y12-AKT Pathway in Pancreatic Cancer Cells

The pro-inflammatory role of platelets in cancer

Bone Marrow Defects and Platelet Function: A Focus on MDS and CLL

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