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10.03.2017 | Original Article

In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension

verfasst von: Bethany Baumgart, Mausumee Guha, James Hennan, Julia Li, Jochen Woicke, Damir Simic, Michael Graziano, Nicola Wallis, Thomas Sanderson, Roderick Todd Bunch

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2017

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Abstract

Purpose

Pulmonary arterial hypertension (PAH) results from occlusion or vasoconstriction of pulmonary vessels, leading to progressive right ventricular failure. Dasatinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myelogenous leukemia, has been associated with PAH. In contrast, the BCR-ABL1 TKI imatinib has demonstrated anti-vasoproliferative properties and has been investigated as a potential treatment for PAH. Here we describe studies evaluating the effects of dasatinib and imatinib on cardiovascular and pulmonary functions to understand the reported differential consequences of the two TKIs in a clinical setting.

Methods

The direct effects of dasatinib and imatinib were explored in vivo to investigate possible mechanisms of dasatinib-induced PAH. In addition, effects of dasatinib and imatinib on PAH-related mediators were evaluated in vitro.

Results

In rats, both TKIs increased plasma nitric oxide (NO), did not induce PAH-related structural or molecular changes in PA or lungs, and did not alter hemodynamic lung function compared with positive controls. Similarly, in the pulmonary artery endothelial cells and smooth muscle cells co-culture model, imatinib and dasatinib increased NO and decreased endothelin-1 protein and mRNA.

Conclusions

The results of these studies indicated that dasatinib did not induce physiological changes or molecular signatures consistent with PAH when compared to positive controls. Instead, dasatinib induced changes consistent with imatinib. Both dasatinib and imatinib induced biochemical and structural changes consistent with a protective effect for PAH. These data suggest that other factors of unclear etiology contributed to the development of PAH in patients treated with dasatinib.

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Baliga RS, MacAllister RJ, Hobbs AJ (2011) New perspectives for the treatment of pulmonary hypertension. Br J Pharmacol 163(1):125–140CrossRefPubMedPubMedCentral

Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R (2013) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 62(25 Suppl):D34–D41CrossRefPubMed

Galie N, Manes A, Branzi A (2004) Evaluation of pulmonary arterial hypertension. Curr Opin Cardiol 19(6):575–581CrossRefPubMed

Levin YD, White RJ (2011) Novel therapeutic approaches in pulmonary arterial hypertension: focus on tadalafil. Drugs Today (Barc) 47 (2):145–156CrossRef

Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G, Guidelines ESCCfP (2009) Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 30(20):2493–2537CrossRefPubMed

Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M (2004) Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43(12 Suppl S):13 S–24 SCrossRef

O’Callaghan DS, Savale L, Montani D, Jais X, Sitbon O, Simonneau G, Humbert M (2011) Treatment of pulmonary arterial hypertension with targeted therapies. Nat Rev Cardiol 8(9):526–538CrossRefPubMed

Price LC, Wort SJ, Perros F, Dorfmuller P, Huertas A, Montani D, Cohen-Kaminsky S, Humbert M (2012) Inflammation in pulmonary arterial hypertension. Chest 141(1):210–221CrossRefPubMed

de Jesus Perez V, Kudelko K, Snook S, Zamanian RT (2011) Drugs and toxins-associated pulmonary arterial hypertension: lessons learned and challenges ahead. Int J Clin Pract Suppl (169):8–10

10.

Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G, Begaud B (1996) Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 335(9):609–616CrossRefPubMed

11.

Hebert VY, Crenshaw BL, Romanoff RL, Ekshyyan VP, Dugas TR (2004) Effects of HIV drug combinations on endothelin-1 and vascular cell proliferation. Cardiovasc Toxicol 4(2):117–131CrossRefPubMed

12.

Talwar A, Sarkar P, Rosen MJ (2009) Pulmonary arterial hypertension in human immunodeficiency virus infection. Postgrad Med 121(5):56–67CrossRefPubMed

13.

Ledinek AH, Jazbec SS, Drinovec I, Rot U (2009) Pulmonary arterial hypertension associated with interferon beta treatment for multiple sclerosis: a case report. Mult Scler 15(7):885–886CrossRefPubMed

14.

Dhillon S, Kaker A, Dosanjh A, Japra D, Vanthiel DH (2010) Irreversible pulmonary hypertension associated with the use of interferon alpha for chronic hepatitis C. Dig Dis Sci 55(6):1785–1790CrossRefPubMedPubMedCentral

15.

Fruehauf S, Steiger S, Topaly J, Ho AD (2001) Pulmonary artery hypertension during interferon-alpha therapy for chronic myelogenous leukemia. Ann Hematol 80(5):308–310CrossRefPubMed

16.

Shah NP, Wallis N, Farber HW, Mauro MJ, Wolf RA, Mattei D, Guha M, Rea D, Peacock A (2015) Clinical features of pulmonary arterial hypertension in patients receiving dasatinib. Am J Hematol 90(11):1060–1064CrossRefPubMed

17.

Wang X, Chai H-T, Lin PH, Yao Q, Chen C (2009) Roles and mechanisms of human immunodeficiency virus protease inhibitor Ritonavir and other anti-human immunodeficiency virus drugs in endothelial dysfunction of porcine pulmonary arteries and human pulmonary artery endothelial cells. Am J Pathol 174(3):771–781CrossRefPubMedPubMedCentral

18.

Rix U, Hantschel O, Durnberger G, Remsing Rix LL, Planyavsky M, Fernbach NV, Kaupe I, Bennett KL, Valent P, Colinge J, Kocher T, Superti-Furga G (2007) Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood 110(12):4055–4063CrossRefPubMed

19.

Mattei D, Feola M, Orzan F, Mordini N, Rapezzi D, Gallamini A (2009) Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient. Bone Marrow Transplant 43(12):967–968CrossRefPubMed

20.

Rasheed W, Flaim B, Seymour JF (2009) Reversible severe pulmonary hypertension secondary to dasatinib in a patient with chronic myeloid leukemia. Leuk Res 33(6):861–864CrossRefPubMed

21.

Hennigs JK, Keller G, Baumann HJ, Honecker F, Kluge S, Bokemeyer C, Brummendorf TH, Klose H (2011) Multi tyrosine kinase inhibitor dasatinib as novel cause of severe pre-capillary pulmonary hypertension? BMC Pulm Med 11:30CrossRefPubMedPubMedCentral

22.

Dumitrescu D, Seck C, ten Freyhaus H, Gerhardt F, Erdmann E, Rosenkranz S (2011) Fully reversible pulmonary arterial hypertension associated with dasatinib treatment for chronic myeloid leukaemia. Eur Respir J 38(1):218–220CrossRefPubMed

23.

Philibert L, Cazorla C, Peyrière H, Mikulski M, Guillemin V, Pinzani-Harter V (2011) Pulmonary arterial hypertension induced by dasatinib: positive reintroduction with nilotinib. Fundam Clin Pharmacol 25(Suppl 1):Abstract 476

24.

Montani D, Bergot E, Gunther S, Savale L, Bergeron A, Bourdin A, Bouvaist H, Canuet M, Pison C, Macro M, Poubeau P, Girerd B, Natali D, Guignabert C, Perros F, O’Callaghan DS, Jais X, Tubert-Bitter P, Zalcman G, Sitbon O, Simonneau G, Humbert M (2012) Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 125(17):2128–2137CrossRefPubMed

25.

Orlandi EM, Rocca B, Pazzano AS, Ghio S (2012) Reversible pulmonary arterial hypertension likely related to long-term, low-dose dasatinib treatment for chronic myeloid leukaemia. Leuk Res 36(1):e4–e6CrossRefPubMed

26.

Sano M, Saotome M, Urushida T, Katoh H, Satoh H, Ohnishi K, Hayashi H (2012) Pulmonary arterial hypertension caused by treatment with dasatinib for chronic myeloid leukemia—critical alert. Intern Med 51(17):2337–2340CrossRefPubMed

27.

Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, Lai YJ, Weissmann N, Seeger W, Grimminger F (2005) Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 115(10):2811–2821CrossRefPubMedPubMedCentral

28.

Pullamsetti SS, Berghausen EM, Dabral S, Tretyn A, Butrous E, Savai R, Butrous G, Dahal BK, Brandes RP, Ghofrani HA, Weissmann N, Grimminger F, Seeger W, Rosenkranz S, Schermuly RT (2012) Role of Src tyrosine kinases in experimental pulmonary hypertension. Arterioscler Thromb Vasc Biol 32(6):1354–1365CrossRefPubMed

29.

Guignabert C, Phan C, Seferian A, Huertas A, Tu L, Thuillet R, Sattler C, Le Hiress M, Tamura Y, Jutant EM, Chaumais MC, Bouchet S, Maneglier B, Molimard M, Rousselot P, Sitbon O, Simonneau G, Montani D, Humbert M (2016) Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. J Clin Invest 126(9):3207–3218CrossRefPubMedPubMedCentral

30.

Ghofrani HA, Morrell NW, Hoeper MM, Olschewski H, Peacock AJ, Barst RJ, Shapiro S, Golpon H, Toshner M, Grimminger F, Pascoe S (2010) Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med 182:1171–1177CrossRefPubMedPubMedCentral

31.

Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galié N, Gómez-Sánchez MA, Grimminger F, Grünig E, Hassoun PM, Morrell NW, Peacock AJ, Satoh T, Simonneau G, Tapson VF, Torres F, Lawrence D, Quinn DA, Ghofrani HA (2013) Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation 127:1128–1138CrossRefPubMed

32.

Al-Naamani N, Roberts KE, Hill NS, Preston IR (2014) Imatinib as rescue therapy in a patient with pulmonary hypertension associated with Gaucher disease. Chest 146:e81–e83CrossRefPubMed

33.

Efficacy, safety, tolerability and pharmacokinetics (pk) of nilotinib (AMN107) in pulmonary arterial hypertension (PAH). http://www.clinicaltrials.gov/ct2/show/NCT01179737. Accessed April 2014

34.

An X, Tiwari AK, Sun Y, Ding PR, Ashby CR Jr, Chen ZS (2010) BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. Leuk Res 34(10):1255–1268CrossRefPubMed

35.

Salih J, Hilpert J, Placke T, Grunebach F, Steinle A, Salih HR, Krusch M (2010) The BCR/ABL-inhibitors imatinib, nilotinib and dasatinib differentially affect NK cell reactivity. Int J Cancer 127(9):2119–2128CrossRefPubMed

36.

Luo FR, Yang Z, Camuso A, Smykla R, McGlinchey K, Fager K, Flefleh C, Castaneda S, Inigo I, Kan D, Wen M-L, Kramer R, Blackwood-Chirchir A, Lee FY (2006) Dasatinib (BMS-354825) pharmacokinetics and pharmacodynamic biomarkers in animal models predict optimal clinical exposure. Clin Cancer Res 12(23):7180–7186CrossRefPubMed

37.

Wolff NC, Ilaria RL (2001) Establishment of a murine model for therapy-treated chronic myelogenous leukemia using the tyrosine kinase inhibitor STI571. Blood 98(9):2808–2816CrossRefPubMed

38.

Ormiston ML, Deng Y, Rundle N, Bendjelloul F, Tsoporis JN, Parker TG, Stewart DJ, Courtman DW (2013) A lymphocyte-dependent mode of action for imatinib mesylate in experimental pulmonary hypertension. Am J Pathol 182(5):1541–1551CrossRefPubMed

39.

Sun C-K, Lee F-Y, Sheu J-J, Yuen C-M, Chua S, Chung S-Y, Chai H-T, Chen Y-T, Kao Y-H, Chang L-T, Yip H-K (2009) Early combined treatment with cilostazol and bone marrow-derived endothelial progenitor cells markedly attenuates pulmonary arterial hypertension in rats. J Pharmacol Exp Ther 330(3):718–726CrossRefPubMed

40.

Li Y, Guo Y, Chen Y, Wang Y, You Y, Yang Q, Weng X, Li Q, Zhu X, Zhou B, Liu X, Gong Z, Zhang R (2015) Establishment of an interleukin-1b-induced inflammation-activated endothelial cell-smooth muscle cell-mononuclear cell co-culture model and evaluation of the anti-inflammatory effects of tanshinone IIA on atherosclerosis. Mol Med Rep 12:1665–1676PubMedPubMedCentral

41.

Acker SN, Seedorf GJ, Abman SH, Nozik-Grayck E, Kuhn K, Partrick DA, Gien J (2015) Altered pulmonary artery endothelial-smooth muscle cell interactions in experimental congenital diaphragmatic hernia. Pediatr Res 77:511–519CrossRefPubMedPubMedCentral

42.

Pirvulescu MM, Gan AM, Stan D, Simion V, Calin M, Butoi E, Manduteanu I (2014) Subendotherlial resistin enhances monocyte transmigration in a co-culture of human endothelial and smooth muscle cells by mechanisms involving fractalkine, MCP-1 and activation of TLR4 and Gi/o proteins signaling. Int J Biochem Cell Biol 50:29–37CrossRefPubMed

43.

Bristol-Myers Squibb C (2016) Sprycel (dasatinib) prescribing information. Bristol-Myers Squibb C, Princeton

44.

Novartis PSA (2015) Gleevec (imatinib) prescribing information. Novartis PSA, Basel

45.

Nagaraj C, Tang B, Balint Z, Wygrecka M, Hrzenjak A, Kwapiszewska G, Stacher E, Lindenmann J, Weir EK, Olschewski H, Olschewski A (2013) Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries. Eur Respir J 41(1):85–95CrossRefPubMed

Titel: In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension
verfasst von: Bethany Baumgart
Mausumee Guha
James Hennan
Julia Li
Jochen Woicke
Damir Simic
Michael Graziano
Nicola Wallis
Thomas Sanderson
Roderick Todd Bunch
Publikationsdatum: 10.03.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2017
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-017-3264-2

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Springer Medizin

In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension

Abstract

Purpose

Methods

Results

Conclusions

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Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

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