Cytotoxic Activity of Apixaban on HeLa Cells: An In vitro Study

Apixaban is a new oral anticoagulant which is commonly used in the prophylaxis and treatment of systemic embolism and deep vein thrombosis. Venous thromboembolic events are important risk factors in cancer patients. Several studies have suggested that anticoagulant drugs may have an effect on tumor development and progression. In this study, we aimed to investigate the cytotoxic effect of apixaban on a cancer cell line HeLa cells derived from human cervical cancer. The viability of HeLa cells was examined at 24 and 48 hours of incubation and apixaban showed a cytotoxic effect in the highest dilution. In other dilutions, cell viability was similar to the control group. These results show that apixaban may reduce proliferation of cancer cells at high concentrations.

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  • A. Di Minno, B Frigerio, G. Spadarella, A. Ravani, D. Sansaro, M. Amato, J.P. Kitzmiller, M. Pepi, E. Tremoli, D. Baldassarre, Old and new oral anticoagulants: Food, herbal medicines and drug interactions. Blood. Rev., 31 (2015) 193-203.
  • C. Frost, J. Wang, S.Nepal, A. Schuster, Y.C. Barrett, R. Mosqueda-Garcia, R.A. Reeves, F. LaCreta, Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. BJCP. 75 (2012) 476-487.
  • G.T. Gerotziafas, I. Mahé, I. Elalamy, New orally active anticoagulant agents for the prevention and treatment of venous thromboembolism in cancer patients. Ther. Clin. Risk. Manag., 10 (2014) 423-426
  • A. Di Minno, B Frigerio, G. Spadarella, A. Ravani, D. Sansaro, M. Amato, J.P. Kitzmiller, M. Pepi, E. Tremoli, D. Baldassarre, Old and new oral anticoagulants: Food, herbal medicines and drug interactions. Blood. Rev., 31 (2015) 193-203.
  • C. Frost, J. Wang, S.Nepal, A. Schuster, Y.C. Barrett, R. Mosqueda-Garcia, R.A. Reeves, F. LaCreta, Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. BJCP. 75 (2012) 476-487.
  • G.T. Gerotziafas, I. Mahé, I. Elalamy, New orally active anticoagulant agents for the prevention and treatment of venous thromboembolism in cancer patients. Ther. Clin. Risk. Manag., 10 (2014) 423-426. Ö.A. Gürpınar et al. / Hacettepe J. Biol. & Chem., 2018, 46 (3), 395–402 401
  • V. Der Hulle, P.L. Den Exter, J. Kooiman, J.J.M. Van der Hoeven, M.V. Heismen, F.A. Klok, Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J. Thromb. Haemost., 12 (2014) 1116-1120.
  • M.N. Levine, C. Gu, H.A. Liebman, C.P. Escalante, S. Solymass, D. Deitchman, L. Ramirez, J. Julian, A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J. Thromb. Haemost., 10 (2012) 807-814.
  • L. Guasti, A. Sqizzato, P. Moretto, D., Vigetti, W. Agero, F. Dentali, A.M. Moresca, L. Campiotti, A.M. Grandi, A. Passi, In vitro effects of Apixaban on 5 different cancer cell lines. PlosOne, 12 (2017) 1-19.
  • T.A. Hambrough, G.M. Swartz, A. Papathanassiu, G.P. Vlasuk, W.E. Rote, S.J. Green, V.S. Pribluda, Tissue Factor/Factor VIIa Inhibitors Block Angiogenesis and Tumor Growth Through a Nonhemostatic Mechanism. Cancer Res., 63 (2003) 2997-3000.
  • J. Ferlay, I. Soerjomataram, R. Dikshit, S. Eser, C. Mathers, M. Rebelo, D. M. Parkin, D. Forman, F. Bray, Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. IJC, 136 (2015) 359-386.
  • S. Takeuchi, Biology and treatment of cervical adenocarcinoma. Chin. J. Cancer Res., 28 (2016) 254- 262.
  • E.C. Pirog, Cervical Adenocarcinoma: Diagnosis of Human Papillomavirus–Positive and Human Papillomavirus–Negative Tumors. Arch. Pathol. Lab. Med. 241 (2017) 1653–1667.
  • J.J. M. Landro, P.T. Pyl, T. Rausch,T. Zichner, M.M. Tekkedil, A.M. Stütz, A. Jauch, R.S. Aiyar, G. Pau, N. Delhomme, J. Gagneur, J.O. Korbel, W. Huber, L.M. Steinmetz, The Genomic and Transcriptomic Landscape of a HeLa Cell Line. Genes Genoms Genetics. 3 (2013) 1213-1224.
  • B.P. Lucey, W.A. Nelson-Rees, G.M. Hutchins, Henrietta Lacks, HeLa Cells, and Cell Culture Contamination. Arch. Pathol. Lab. Med. 133 (2009) 1463–1467.
  • J.M.E. Contreras-Ortiz, J.C. Vázquez-Chagoyán, J.S. Martínez-Castañeda, J.G. Estrada-Franco, J.E. Aparicio-Burgos, J. Acosta-Dibarrat, A. BarbabosaPliego, Resistance of cervical adenocarcinoma cells (HeLa) to venom from the scorpion Centruroides limpidus limpidus. JVATITD. 19 (2013) 1-7.
  • P.C. Wong, D.J.P. Pinto, D. Zhang, Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J. Thromb. Thrombolysis. 31 (2011) 478–492.
  • P.C. Wong, E.J. Crain, B. Xin, R.R. Wexler, P.Y.S. Lam, D.J. Pinto, J.M. Luettgen, R.M. Knabb, Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J. Thromb. Haemost. 6 (2007) 820-829.
  • J.M. Luettegen, R.M. Knabb, K. He, D.J.P. Pinto, A.R. Rendia, Apixaban inhibition of factor Xa: Microscopic rate constants and inhibition mechanism in purified protein systems and in human plasma. J. Enzym. Inhib. Med. Ch. 26 (2011) 514-526.
  • D.J. Pinto, M.J. Orwatt, S. Koch, K.A. Rossi, R.S. Alexander, A. Smallwood, P.C. Wong, A.R. Rendina, J.M. Luettegen, R.M. Knabb, K. He, B. Xin, R.R. Wexler, P.Y. Lam, Discovery of 1-(4-methoxyphenyl)-7-oxo6-(4-(2-oxopiperidin-1-yl)phenyl) -4,5,6,7-tetrahydro1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban,BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J. Med. Chem. 50 (2007) 5339-5356.
  • R. Alam, D. Wahi, R. Singh, D. Sinha, V. Tandan, A. Graver, Rahisuddin, Design, synthesis, cytotoxicity, HuTopoIIa inhibitory activity and molecular docking studies of pyrazole derivatives as potential anticancer agents. Bioorg. Chem. 69 (2016) 77-90.
  • A.T. Baviskar, C. Madaan, P. Mohaptra, V. Jain, A. Agrawal, S.K. Guchhait, C.N. Kundu, U.C. Banerjee, N-Fused Imidazoles As Novel Anticancer Agents That Inhibit Catalytic Activity of Topoisomerase IIr and Induce Apoptosis in G1/S Phase. J. Med. Chem. 54 (2011) 5013-5030.
  • J.J. Champoux, DNA Topoisomerases: Structure, Function, and Mechanism. Annu. Rev. Biochem. 70 (2001) 369-413.
  • R. Alam, A. Alam, A.K. Panda, Rahisuddin, Design, synthesis and cytotoxicity evaluation of pyrazolyl pyrazoline and pyrazolyl aminopyrimidine derivatives as potential anticancer agents. Med. Chem. Res.27 (2018) 560–570.
  • H. Li, X. Wu, X. Cheng, Advances in diagnosis and treatment of metastatic cervical cancer. J. Gynecol. Oncol. 27 (2016) 1-20.
  • S.J. Tsai, Y.X. Ruan, C.C. Lee, M.S. Lee, W.Y. Chiou, H.Y. Lin, F.C. Hsu, Y.C. Su, S.K. Hung, The incidence of venous thromboembolism in cervical cancer: a nationwide population-based study. BMC Research Notes. 5 (2012) 316-321.
  • G. Agnelli, H.R. Buller, A. Cohen, A.S. Gallus, T.C. Lee, R. Pak, G.E. Raskob, J.I. Weitz, T. Yamabe Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J. Thromb. Haemost. 13 (2015) 2187-2191.
  • J.S. Palumbo, K.W. Kombrinck, A.F. Drew, T.S. Grimes, J.H. Kiser, J.L. Degen, T.H. Bugge, Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood. 96 (2000) 3302-3309.
  • T.A. Hembrough, G.M. Swartz, A. Papathanassiu, G.P. Vlasuk, W.E. Rote, S.J. Green, V.S. Pribluda, Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism. Cancer. Res. 63 (2003) 2997-3000.
  • J.S. Ventura, F. Faria, I.F.C. Batista, S.M. Simons, D.G.L. Oliveira, K.L.P. Morais, A.M. Chudzinski-Tavassi, A Kunitz-type FXa inhibitor affects tumor progression, hypercoagulable state and triggers apoptosis. Biomed Pharmacother. 67 (2013) 192-196.
  • A.C. Matzdorff, D. Green, Coagulation in Cancer, Springer Science Business Media, 2009.
  • N. Zhang, W. Lou, F. Ji1, L. Qiu, B.K. Tsang, W. Di, Low molecular weight heparin and cancer survival: clinical trials and experimental mechanisms. J. Cancer Res. Clin. Oncol. 142 (2016) 1806-1816.
  • E.L. Hellenbart, K.D. Faulkenberg, S.W. Finks, Evaluation of bleeding in patients receiving direct oral anticoagulants. Vasc. Health Risk. Manag. 13 (2017) 325-342.
  • N.E. Núñez-Navarro, G.F. S. Renato A. Burgos, C.F. Lagos, N. Fuentes-Ibacache, M.A. Faúndezb, F.C. Zacconi, Microwave Assisted Synthesis of Novel SixMembered 4-C, 4-O and 4-S Lactams Derivatives: Characterization and in vitro Biological Evaluation of Cytotoxicity and Anticoagulant Activity. J. Braz. Chem. Soc., 28 (2017) 203-207.