Abstract Number: PB1796
Meeting: ISTH 2020 Congress
Background: Ticagrelor is an inhibitor of P2Y12, a receptor primarily found on platelets. The drug is used to reduce the risk of thrombotic complications in patients with cardiovascular diseases. Recent clinical data suggest that ticagrelor is associated with a lower incidence of solid tumours.
Aims: To investigate direct anticancer activities of ticagrelor and the possible underlying mechanisms.
Methods: Anti-proliferative activity of ticagrelor in vitro was assessed in pancreatic cancer cells AsPC-1, BxPC-3, MiaPaCa-2, PANC1 and CFPAC-1 and the normal pancreatic duct cell line, hTERT-HPNE. The Caspase 3/7 activity, Annexin-V binding, and anti-apoptotic protein BCL-XL detection assays were used to investigate ticagrelor-induced apoptosis. P2Y12-mediated signal transduction was studied using siRNA knockdown strategies and pharmacological inhibitors. The benefits of ticagrelor as an additional treatment to chemotherapy was assessed in vitro and in a xenograft and syngeneic murine models of pancreatic cancer.
Results: Ticagrelor displayed anticancer activity in vitro with IC50s less than 10 µM; the maximum tolerated plasma concentration in humans. Ticagrelor up to 20 µM did not affect the growth of non-malignant hTERT-HPNE. Ticagrelor at 2.5 and 5 µM significantly reduced Akt activation and activated apoptosis in pancreatic cancer cells, respectively (N ≥ 4). Interestingly, P2Y12 expression was observed in pancreatic cancer cells and was important in mediating epidermal growth factor receptor-dependent and independent-Akt activation. Ticagrelor (2.5 µM) showed synergistic action with gemcitabine, paclitaxel, cisplatin, and erlotinib in pancreatic cancer cells in vitro. Combined with gemcitabine (25 mg/kg per week), ticagrelor (100 mg/kg per day) significantly reduced tumour growth in vivo (N ≥ 5, p < 0.033), whereas gemcitabine alone had a non-statistically significant effect.
Conclusions: Our findings revealed a novel anticancer effect of ticagrelor and a critical role of P2Y12 signalling on cancer cells which may partly explain the reduced solid tumour incidence in patients receiving ticagrelor in clinical studies.
To cite this abstract in AMA style:Elaskalani O, Metharom P. Anti-Platelet Drug Ticagrelor Has a Direct Anticancer Activity [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/anti-platelet-drug-ticagrelor-has-a-direct-anticancer-activity/. Accessed November 29, 2023.
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