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May warfarin prevent cancer?


Authors: Anna Remková 1;  Milan Remko 2
Authors‘ workplace: I. interná klinika LF SZU a UNB, Nemocnica akademika Ladislava Dérera, Bratislava, Slovenská republika 1;  Remedika, s. r. o., Bratislava, Slovenská republika 2
Published in: Vnitř Lék 2019; 65(11): 679-684
Category:

Overview

Animal and epidemiologic studies suggest that the use of warfarin might reduce cancer incidence. The antitumor potential of warfarin is demonstrated in different experimental cancer models. Specifically, studies in murine cancer models have shown that warfarin blocks AXL receptor tyrosine kinase by inhibiting a vitamin K-dependent protein called GAS6, thereby may halt the spread of cancer cells. An off-target effect of the anticoagulant warfarin is inhibition of GAS6-AXL signaling, which enhances antitumor immunity and blocks tumorigenesis independently of anticoagulation. Hence, the observed association between warfarin use and lower cancer incidence is likely due to an enhanced antitumor immune surveillance of early cancer. The large observational study also showed a reduction in cancer incidence among regular warfarin users. The study data indicate that warfarin provides a possible cancer protection. Despite some limitations, the results of this study give further support for the hypothesis that warfarin use decreases cancer incidence, which warrants continued investigation. This finding may have important implications for choosing medications in patients who need anticoagulant therapy.

Keywords:

warfarin – antitumor immune surveillance – AXL receptor tyrosine kinase – cancer incidence


Sources
  1. Zacharski LR. Anticoagulants in cancer treatment: malignancy as a solid-phase coagulopathy. Cancer Lett 2002; 186(1): 1–9. Dostupné z DOI: <http://dx.doi.org/10.1016/s0304–3835(02)00258–6>.
  2. Zacharski LR, Prandoni P, Monreal M. Warfarin versus Low-molecular-weight heparin therapy in cancer patients. Oncologist 2005; 10(1): 72–79. Dostupné z DOI: <http://dx.doi.org/10.1634/theoncologist.10–1-72>.
  3. Remková A, Remko M. Antitrombotiká v klinickej praxi. Samedi: Bratislava 2014. ISBN 9788097082581.
  4. Keeling D, Baglin T, Tait C et al. British Committee for Standards in Haematology. Guidelines on oral anticoagulation with warfarin – fourth edition. Br J Haematol 2011; 154(3): 311–324. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1365–2141.2011.08753.x>.
  5. Dossett LA, Riesel JN, Griffin MR et al. Prevalence and implications of preinjury warfarin use: an analysis of the National Trauma Databank. Arch Surg 2011; 146(5): 565–570. Dostupné z DOI: <http://dx.doi.org/10.1001/archsurg.2010.313>.
  6. Haaland GS, Falk, RS, Straume O et al. Association of warfarin use with lower overall cancer incidence among patients older than 50 years. JAMA Intern Med 2017; 177(12): 1774–1780. Dostupné z DOI: <http://dx.doi.org/10.1001/jamainternmed.2017.5512>.
  7. McCulloch P, George WD. Warfarin inhibition of metastasis: the role of anticoagulation. Br J Surg 1987; 74(10): 879–883. Dostupné z DOI: <http://dx.doi.org/10.1002/bjs.1800741005>.
  8. Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. N Engl J Med 2000; 342(26): 1953–1958. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJM200006293422604>.
  9. Ryan JJ, Ketcham AS, Wexler H. Reduced incidence of spontaneous metastases with long-term Coumadin therapy. Ann Surg 1968; 168(1): 163–168. Dostupné z DOI: <http://dx.doi.org/10.1097/00000658–196807000–00021>.
  10. Williamson RC, Lyndon PJ, Tudway AJ. Effects of anticoagulation and ileal resection on the development and spread of experimental intestinal carcinomas. Br J Cancer 1980; 42(1): 85–94. Dostupné z DOI: <http://dx.doi.org/10.1038/bjc.1980.206>.
  11. Zacharski LR, Ornstein DL. Heparin and cancer. Thromb Haemost 1998; 80(1): 10–23.
  12. Zacharski LR, Ornstein DL, Mamourian AC. Low-molecular-weight heparin and cancer. Semin Thromb Hemost 2000; 26(Suppl 1): 69–77.
  13. Paolino M, Choidas A, Wallner S et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 2014; 507(7493): 508–512. Dostupné z DOI: <http://dx.doi.org/10.1038/nature12998>.
  14. Kirane A, Ludwig KF, Sorrelle N et al. Warfarin blocks Gas6-mediated Axl activation required for pancreatic cancer epithelial plasticity and metastasis. Cancer Res 2015; 75(18): 3699–3705. Dostupné z DOI: <http://dx.doi.org/10.1158/0008–5472.CAN-14–2887-T>.
  15. Tagalakis V, Tamim H, Blostein M et al. Use of warfarin and risk of urogenital cancer: a population-based, nested case-control study. Lancet Oncol 2007; 8(5): 395–402. Dostupné z DOI: <http://dx.doi.org/10.1016/S1470–2045(07)70046–3>.
  16. Kinnunen PT, Murtola TJ, Talala K et al. Warfarin use and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer. Scand J Urol 2016; 50(6): 413–419. Dostupné z DOI: <http://dx.doi.org/10.1080/21681805.2016.1228085>.
  17. Zacharski LR, Henderson WG, Rickles FR et al. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate: final report of VA Cooperative Study #75. Cancer 1984; 53(10): 2046–2052. Dostupné z DOI: <http://dx.doi.org/10.1002/1097–0142(19840515)53:10<2046::aid-cncr2820531007>3.0.co;2-f>.
  18. Chahinian AP, Propert KJ, Ware JH et al. A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. J Clin Oncol 1989; 7(8): 993–1002. Dostupné z DOI: <http://dx.doi.org/10.1200/JCO.1989.7.8.993>.
  19. Aisner J, Goutsou M, Maurer LH et al. Intensive combination chemotherapy, concurrent chest irradiation, and warfarin for the treatment of limited-disease small-cell lung cancer: a Cancer and Leukemia Group B pilot study. J Clin Oncol 1992; 10(8): 1230–1236. Dostupné z DOI: <http://dx.doi.org/10.1200/JCO.1992.10.8.1230>.
  20. Maurer LH, Herndon JE, Hollis DR et al. Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a Cancer and Leukemia Group B study. J Clin Oncol 1997; 15(11): 3378–3387. Dostupné z DOI: <http://dx.doi.org/10.1200/JCO.1997.15.11.3378>.
  21. Thodiyil P, Kakkar AK. Can low-molecular-weight heparins improve outcomes in patients with cancer? Cancer Treat Rev 2002; 28(3): 151–155.
  22. Buijs JT, Laghmani EH, van den Akker RFP et al. The direct oral anticoagulants rivaroxaban and dabigatran do not inhibit orthotopic growth and metastasis of human breast cancer in mice. J Thromb Haemost 2019; 17(6): 951–963. Dostupné z DOI: <http://dx.doi.org/10.1111/jth.14443>.
  23. Meyer G, Besse B, Doubre H et al. Anti-tumour effect of low molecular weight heparin in localised lung cancer: a phase III clinical trial. Eur Respir J 2018; 52(4). pii: 1801220. Dostupné z DOI: <http://dx.doi.org/10.1183/13993003.01220–2018>.
  24. Hirsh J, Dalen J, Anderson DR et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119(Suppl): S8-S21. Dostupné z DOI: <http://dx.doi.org/10.1378/chest.119.1_suppl.8s>.
  25. Cranenburg EC, Schurgers LJ, Vermeer C. Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost 2007; 98(1): 120–125.
  26. Davra V, Kimani SG, Calianese D et al. Ligand activation of TAM family receptors – implications for tumor biology and therapeutic response. Cancers (Basel) 2016; 8(12). pii: E107. Dostupné z DOI: <http://dx.doi.org/10.3390/cancers8120107>.
  27. Song X, Wang H, Logsdon CD et al. Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma. Cancer 2011; 117(4): 734–743. Dostupné z DOI: <http://dx.doi.org/10.1002/cncr.25483>.
  28. Hasanbasic I, Rajotte I, Blostein M. The role of gamma-carboxylation in the anti-apoptotic function of gas6. J Thromb Haemost 2005; 3(12): 2790–2797. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1538–7836.2005.01662.x>.
  29. Hafizi S, Dahlback B. Gas6 and protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily. FEBS J 2006; 273(23): 5231–5244. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1742–4658.2006.05529.x>.
  30. Tsou WI, Nguyen KQ, Calarese DA et al. Receptor tyrosine kinases, TYRO3, AXL, and MER, demonstrate distinct patterns and complex regulation of ligand-induced activation. J Biol Chem 2014; 289(37): 25750–25763. Dostupné z DOI: <http://dx.doi.org/10.1074/jbc.M114.569020>.
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Diabetology Endocrinology Internal medicine

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