Antitumor proteinkinase inhibitor imatinib may be regarded as a potential correcting agent for COVID-19 associated pulmonary fibrosis
https://doi.org/10.17650/2313-805X-2020-7-4-20-28
Abstract
Imatinib mesilate is a well-known antitumor target inhibitor of protein tyrosine kinase, which is effective in different cancer types expressing Bcr / Abl and, in particular, in hemoblastosis. A higher interest to imatinib during the COVID-19 epidemic is explained by the fact that cancer patients are one of the COVID-19 risk groups. Moreover, imatinib target mechanism of action, which is effective in cancer, can have a high potential against the most severe COVID-19 complication such as the disease associated pulmonary fibrosis. COVID-19 associated interstitial pulmonary fibrosis develops as an autoimmune process caused by systemic inflammation with atypical (idiopathic) pneumonia resulting from acute respiratory distress syndrome with the tyrosine kinase mechanism of signaling pathway activation and cellular response. Experi-mental and clinical results showing antifibrotic and dose-related antithrombotic imatinib effect demonstrate perspective use of this antitumor agent to correct COVID-19 associated pneumonia causing a high death rate of patients with COVID-19.
The review presents literature data of 2001–2020 discussing pathologic genetic and clinical characteristics of the fibrosis which exacerbates COVID-19 pneumonia in adults. The sequence of the disease processes demonstrates that disease progression with the decreasing oxygen saturation in the peripheral blood intensifies local thrombosis in the lungs. As a result, hypoxia is developing, which is difficult to control and can cause lethal outcome in severe cases. Yet, the conventional antifibrotic and thrombolytic agents can only partially control the process of pneumofibrosis including that of cancer patients. The approximate antifibrotic dose of imatinib 400 mg / day is therapeutic for oncopatho-logy. The antitumor drug registered in many countries and well described side effects and contraindications needs no long-term registration studies for a new indication, therefore, it may be easily prepared for clinical testing.
About the Authors
I. N. MikhaylovaRussian Federation
24 Kashirskoe Shosse, Moscow 115478
N. M. Treshalina
Russian Federation
24 Kashirskoe Shosse, Moscow 115478
I. Zh. Shubina
Russian Federation
24 Kashirskoe Shosse, Moscow 115478
I. V. Manina
Russian Federation
Build. 1, 20 Malaya Bronnaya St., Moscow 123104
M. V. Kiselevsky
Russian Federation
24 Kashirskoe Shosse, Moscow 115478
A. N. Lukashev
Russian Federation
Build. 1, 20 Malaya Pirogovskaya St., Moscow 119435
References
1. Cobbaut M., Derua R., Döppler H. et al. Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved tyr in the P+1 loop. Sci Rep 2017;7(1):887. DOI: 10.1038/s41598-017-00800-w.
2. Letsiou E., Rizzo A.N., Sammani S. et al. Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 2015;308(3):L259–69. DOI: 10.1152/ajplung.00323.2014.
3. Li M., Abdollahi A., Gröne H.J. et al. Late treatment with imatinib mesylate ameliorates radiation-induced lung fibrosis in a mouse model. Radiat Oncol 2009;66(4):1–9. DOI: 10.1186/1748-717X-4-66.
4. Vuorinen K., Gao F., Oury T.D. et al. Imatinib mesylate inhibits fibrogenesis in asbestosinduced interstitial pneumonia. Exp Lung Res 2007;33(7):357–73. DOI: 10.1080/01902140701634827.
5. Wolf A.M., Wolf D., Rumpold H. et al. The kinase inhibitor imatinib mesylate inhibits TNFα production in vitro and prevents TNF-dependent acute hepatic inflammation. Proc Natl Acad Sci USA 2005;102:13622–7. DOI: 10.1073/PNAS.0501758102.
6. McGonagle D., Sharif K., O’Regan A.Ch. The Role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev 2020;19(6):102537. DOI: 10.1016/j.autrev.2020.102537.
7. Mehta P., McAuley D.F., Brown M. et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395(10229):1033–4. DOI: 10.1016/S0140-6736(20)30630-9.
8. Karakike E., Giamarellos-Bourboulis E.J. Macrophage activation-like syndrome: a distinct entity leading to early death in sepsis. /Front Imunol 2019;10:55. DOI: 10.3389/fimmu.2019.00055.
9. Berlin A.A., Lukacs N.W. Treatment of cockroach allergen asthma model with imatinib attenuates airway responses. Am J Respir Crit Care Med 2005;171(1):35–9. DOI: 10.1164/rccm.200403-385OC.
10. Baron F., Turhan A.G., Giron-Michel J. et al. Leukemic target susceptibility to natural killer cytotoxicity: relationship with BCR-ABL expression. Blood 2002;99:2107–13. DOI: 10.1182/blood.v99.6.2107.
11. Nakamura Y., Yamashita M., Yamauchi K., Sawai T. Effects of imatinib mesylate on pulmonary allergic vasculitis in a murine model. Int J Rheumatic Dis 2013;16:455–62. DOI: 10.1111/1756-185X.12075.
12. Paniagua R.T., Sharpe O., Ho P.P. et al. Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J Clin Inv 2006;116:2633–42. DOI: 10.1172/JCI28546.
13. Успенская Ю.А., Комлева Ю.К., Горина Я.В. и др. Полифункциональность CD147 и новые возможности для диаг- ностики и терапии. Сибирское меди- цинское обозрение 2018;(4):22–30. [Uspenskaya Yu.A., Komleva Yu.K., Gorina Ya.V. et al. CD147 poly functi o- nality and new diagnostic and therapy opportunities. Sibirskoye meditsinskoye obozrenie = Siberian Medical Review 2018;(4):22–30. (In Russ.)]. DOI: 10.20333/2500136-2018-4-22-30.
14. Liang L., Major T., Bocan T. Characterization of the promoter of human extracellular matrix metalloproteinase inducer (EMMPRIN). Gene 2002;282(1): 75–86. DOI: 10.1016/s0378-1119(01)00847-2.
15. Yang H., Zou W., Chen B. Overexpression of CD147 in ovarian cancer is initiated by the hypoxic microenvironment. Cell Biol Int. 2013;37(10):1139–42. DOI: 10.1002/cbin.10131.
16. Huang C., Wang Y., Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497–506. DOI: 10.1016/s0140-736(20)30183-5.
17. Vaninov N. In the eye of the COVID-19 cytokine storm. Nat Rev Immunol 2020 [ahead of print]. DOI: 10.1038/s41577-020-0305-6.
18. Magro C.J., Mulvey J., Berlin D. et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res 2020;220:1–13. DOI: 10.1016/j.trsl.2020.04.007.
19. Thille A.W., Esteban A., Fernández-Segoviano P. et al. Chronology of histological lesions in acute respiratory distress syndrome with diffuse alveolar damage: a prospective cohort study of clinical autopsies. Lancet Respir Med 2013;1:395–401. DOI: 10.1016/S2213-2600(13)70053-5.
20. Merad M., Martin J.C. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol 2020;20(6):355–62. DOI: 10.1038/s41577-020-0331-4.
21. Siddiqi H.K., Mehra M.R. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant 2020;39:405–7. DOI: 10.1016/j.healun.2020.03.012.
22. Cardinal-Fernández P., Lorente J.A., Ballén-Barragán A., Matute-Bello G. Acute respiratory distress syndrome and diffuse alveolar damage. New insights on a complex relationship. Ann Am Thorac Soc 2017;14:844–50. DOI: 10.1513/AnnalsATS.201609-728PS.
23. Pittet J.F., Griffiths M.J., Geiser T. et al. TGF-β is a critical mediator of acute lung injury. J Clin Invest 2001;107:1537–44. DOI: 10.1172/JCI11963.
24. Cao Ch., Leng Yu., Li Ch., Kufe D. Functional interaction between the c-Abl and Arg protein-tyrosine kinases in the oxidative stress response. J Biol Chem 2003;11;278(15):12961–7. DOI: 10.1074/jbc.M300058200.
25. George P.M., Wells A.U., Jenkins R.G. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med 2020(8):807–15. DOI: 10.1016/S2213-2600(20)30225-3.
26. Cordeiro C.R., Campos P., Carvalho L. et al. Consensus document for the diagnosis and treatment of idiopathic pulmonary fibrosis. Revista Portuguesa de Pneumologia (English Edition) 2016;22(2):112–22. DOI: 10.1016/j.rppnen.2016.01.003.
27. Marchandot B., Trimaille A., Curtiaud A. et al. Thromboprophylaxis: balancing evidence and experience during the COVID-19 pandemic. J Thromb Thrombolysis 2020;50(4):799–808. DOI: 10.1007/s11239-020-02231-3.
28. Aman J., Peters M.J., Weenink C. et al. Reversal of vascular leak with imatinib. Am J Respir Crit Care Med 2013;188:1171–3. DOI: 10.1164/rccm.201301-0136LE.
29. Aman J., van Bezu J., Damanafshan A. et al. Effective treatment of edema and endothelial barrier dysfunction with imatinib. Circulation 2012;126:2728–38. DOI: 10.1161/circulationaha.112.134304.
30. Chislock E.M., Pendergast A.M. Abl family kinases regulate endothelial barrier function in vitro and in mice. PLoS One 2013;8:e85231. DOI: 10.1371/journal.pone.0085231.
31. Ciarcia R., Vitiello M.T., Galdiero M. et al. Imatinib treatment inhibit IL-6, IL-8, NF-κB and AP-1 production and modulate intracellular calcium in CML patients. J Cell Physiol 2012;227: 2798–803. DOI: 10.1002/jcp.23029.
32. Shlyakhtychenko T.Yu. The cytokine status in pathogenesis and treatment of chronic myeloid leukemia. Gematologiya. Transfuziologiya. Vostochnaya Evropa = Hematology. Transfusiology. Eastern Europe 2015;(3):112–9. (In Russ.).
33. Rhee C.K., Lee S.H., Yoon H.K. et al. Effect of nilotinib on bleomycin-induced acute lung injury and pulmonary fibrosis in mice. Respiration 2011;82:273–87. DOI: 10.1159/000327719.
34. Napier R.J., Norris B.A., Swimm A. et al. Low doses of imatinib induce myelopoiesis and enhance host anti-microbial immunity. PLoS Pathogens 2015;11(3):e1004770. DOI: 10.1371/journal.ppat.1004770.
35. Klok F.A., Kruip M.J.H.A., van der Meer N.J.M. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020;191:145–7. DOI: 10.1016/j.thromres.2020.04.013.
36. Poissy L., Goutay J., Caplan M. et al. Pulmonary embolism in patients with COVID-19: Awareness of an Increased Prevalence. Circulation 2020;142(2):184–6. DOI: 10.1161/circulationaha. 120. 047430.
37. Zhang Y., Meng Xiao M., Zhang Sh. et al. Coagulopathy and antiphospholipid antibodies in patients with COVID-19. N Engl J Med 2020;382(17):e38. DOI: 10.1056/NEJMc2007575.
38. Fogarty H., Townsend L., Cheallaigh C.N. et al. COVID19 coagulopathy in Caucasian patients. Br J Haematol 2020; 189(6): 1044–9. DOI: 10.1111/bjh.16749.
39. Varga Z., Flammer A.J., Steiger P. et al. Electron microscopy of SARS-CoV-2: a challenging task – Authors’ reply. Lancet 2020;395(10238):e100. DOI: 10.1016/S0140-6736(20)31185-5.
40. Paranjpe I., Fuster V., Lala A. et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol 2020;76(1):122–4. DOI: 10.1016/j.jacc.2020.05.001.
41. Grimminger F., Andreas Günther A., Vancheri C. The role of tyrosine kinases in the pathogenesis of idiopathic pulmonary fibrosis. Eur Respir J 2015;45(5):1426–33. DOI: 10.1183/09031936.00149614.
42. Gomer R.H., Lupher M.L.Jr. Investigational approaches to therapies for idiopathic pulmonary Fibrosis. Expert Opin Investig Drugs 2010;19(6):737–45. DOI: 10.1517/13543784.2010.484018.
43. Fraticelli P., Gabrielli B., Pomponio G. et al. Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclo phos-pha mide: a phase II pilot study. Arthritis Res Ther 2014;16(4):R144. DOI: 10.1186/ar4606.
44. Spiera R.F., Gordon J.K., Mersten J.N. et al. Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial. Ann Rheum Dis 2011;70:1003–9. DOI: 10.1136/ard.2010.1439741003.
45. Yang K., Sheng Yu., Huang Ch. et al. Clinical characteristics, outcomes, and risk factors for mortality in patients with cancer and COVID-19 in Hubei, China: a multicentre, retrospective, cohort study. Published online May 29, 2020. Available at: https://doi.org/10.1016/S1470-2045(20)30310-7.
46. Meng Yi., Lu W., Guo E. et al. Cancer history is an independent risk factor for mortality in hospitalized COVID-19 patients: a propensity score-matched analysis. J Hematol Oncol 2020;13:75. DOI: 10.1186/s13045-020-00907-0.
47. ClinicalTrials.gov Identifier: NCT04356495. Treatments to Decrease the Risk of Hospitalization or Death in Elderly Outpatients With Symptomatic SARS-CoV-2 Infection (COVID-19) (COVERAGE). Available at: https://clini-caltrials.gov/ct2/show/NCT04356495.
48. Poddubnaya I.V., Sychev D.A., Abuzarova G.R. et al. Cancer patient management during the COVID-19 pandemic. Training module. Version 2 from 30.04.2020. Sovremennaya onkologiya = Modern Oncology 2020;22(2):56–73. (In Russ.). DOI: 10.26442/18151434.2020.2.200138.
49. Marchandot B., Sattler L., Jesel L., Matsushita K. COVID-19 related coagulopathy: a distinct entity? J Clin Med 2020;9:1651–5. DOI: 10.3390/jcm9061651.
50. Hunt B., Retter A., McClintock C. Practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with COVID-19. Available at: https://thrombosisuk.org/downloads/T&H%20and%20COVID. pdf(accessed on 28 April 2020).
51. Casini A., Alberio L., Angelillo-Scherrer A. et al. Thromboprophylaxis and laboratory monitoring for in-hospital patients with COVID-19-a Swiss consensus statement by the Working Party Hemostasis. Swiss Med Wkly 2020;150: w20247. DOI: 10.4414/smw.2020.20247.
52. Cordeiro C.R., Campos P., Carvalho L. et al. Consensus document for the diagnosis and treatment of idiopathic pulmonary fibrosis: Joint Consensus of Sociedade Portuguesa de Pneumologia, Sociedade Portuguesa de Radiologia e Medicina Nuclear e Sociedade Portuguesa de Anatomia Patológica. Rev Port Pneumol 2016;22(2):112–22. DOI: 10.1016/j.rppnen.2016.01.003
Review
For citations:
Mikhaylova I.N., Treshalina N.M., Shubina I.Zh., Manina I.V., Kiselevsky M.V., Lukashev A.N. Antitumor proteinkinase inhibitor imatinib may be regarded as a potential correcting agent for COVID-19 associated pulmonary fibrosis. Advances in Molecular Oncology. 2020;7(4):20-28. (In Russ.) https://doi.org/10.17650/2313-805X-2020-7-4-20-28