Skip to main content

Advertisement

SpringerLink
Log in

Nilotinib, a tyrosine kinase inhibitor exhibits protection against acute pancreatitis-induced lung and liver damage in rats

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

This investigation explored the nilotinib action in the management of acute pancreatitis (AP) and AP-induced lung and liver injury. AP was induced in Sprague Dawley (SD) rats with L-arginine. Treatment with nilotinib with or without L-arginine was applied for 7 days. Marked deterioration in serum amylase, lipase, aspartate amino transferase (AST), alanine amino transferase (ALT), lactate dehydrogenase (LDH), nitric oxide (NO), total protein content, and transforming growth factor beta1 (TGF-β1) along with pancreatic, hepatic, and pulmonary tissue lipid peroxidation (MDA) after induction of AP while significant reduction in tissues superoxide dismutase (SOD), glutathione (GSH) with marked edema, hemorrhage, and perivascular inflammation with acinar cell necrosis, along with elevated pancreatic percentage expression of TGF-β1 and nuclear factor kappa B (NF-κB), were observed in the AP group. Nilotinib markedly ameliorated biochemical and histopathologic changes during AP, thus preserving the pancreas, liver, and lung histologically through mechanism involving antioxidant and anti-inflammatory actions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Akbarshahi H, Sam A, Chen C, Rosendahl AH, Andersson R (2014) Early activation of pulmonary TGF-β1/Smad2 signaling in mice with acute pancreatitis-associated acute lung injury. Mediat Inflamm 2014:148029. doi:10.1155/2014/148029

    Article  Google Scholar 

  • Akhmetshina A, Dees C, Pileckyte M, Maurer B, Axmann R, Jüngel A, Zwerina J, Gay S, Schett G, Distler O, Distler JH (2008) Dual inhibition of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis. FASEB J 22:2214–2222

    Article  CAS  PubMed  Google Scholar 

  • Andican G, Gelisgen R, Unal E, Tortum OB, Dervisoglu S, Karahasanoglu T, Burçak G (2005) Oxidative stress and nitric oxide in rats with alcohol-induced acute pancreatitis. World J Gastroenterol 11(15):2340–2345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baddeley R, Skipworth J, Pereia S (2010) Acute pancreatitis. Medicine 39:108–115

    Article  Google Scholar 

  • Balachandra S, Genovese T, Mazzon E, Di Paola R, Thiemerman C, Siriwardena AK, Cuzzocrea S (2005) Inhibition of tyrosine-kinase mediated cellular signaling by tyrphostins AG 126 and AG556 modulates murine experimental acute pancreatitis. Surgery 138:913–923

    Article  PubMed  Google Scholar 

  • Bradley EL (1993) A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, Ga, September 11 through 13, 1992. Arch Surg 128:586–590

    Article  PubMed  Google Scholar 

  • Breccia M, Alimena G (2010) Nilotinib: a second-generation tyrosine kinase inhibitor for chronic myeloid leukemia. Leuk Res 34:129–134

    Article  CAS  PubMed  Google Scholar 

  • Campo GM, Avenoso A, Campo S, Nastasi G, Traina P, D’ Ascola A, Calatroni A (2008) Chondroitin-4- sulphate reduced oxidative injury in caerulein-induced pancreatitis in mice: the involvement of NF-kappaB translocation and apoptosis activation. Exp Biol Med (Maywood) 233:741–752

    Article  CAS  Google Scholar 

  • Cappell SM (2008) Acute pancreatitis: etiology, clinical presentation, diagnosis, and therapy. Med Clin N Am 92:889–923

    Article  CAS  PubMed  Google Scholar 

  • Cuzzocrea S, Mazzon E, Dugo L, Serraino I, Centorrino T, Ciccolo A, Van de Loo FA, Britti D, Caputi AP, Thiemermann C (2002) Inducible nitric oxide synthase-deficient mice exhibit resistance to the acute pancreatitis induced by cerulein. Shock 17:416–422

    Article  PubMed  Google Scholar 

  • Czako L, Takacs T, Varga IS, Hai DQ, Tiszlavicz L, Hegyi P, Mandi Y, Matkovics B, Lonovics J (2000) The pathogenesis of L-arginine-induced acute necrotizing pancreatitis: inflammatory mediators and endogenous cholecystokinin. J Physiol Paris 94:43–50

    Article  CAS  PubMed  Google Scholar 

  • Dabrowski A, Konturek SJ, Konturek JW, Gabryelewicz A (1999) Role of oxidative stress in the pathogenesis of caerulein-induced acute pancreatitis. Eur J Pharmacol 377:1–11

    Article  CAS  PubMed  Google Scholar 

  • Day E, Waters B, Spiegel K, Alnadaf T, Manley PW, Buchdunger E, Walker C, Jarai G (2008) Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib. Eur J Pharmacol 599:44–53

    Article  CAS  PubMed  Google Scholar 

  • DiDonato JA, Mercurio F, Karin M (1995) Phosphorylation of I kappa B alpha precedes but is not sufficient for its dissociation from NF-kappa B. Mol Cell Biol 15:1302–1311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • El-Agamy DS (2011) Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats. Toxicol Appl Pharmacol 253:153–160

    Article  CAS  PubMed  Google Scholar 

  • Elsherbiny NM, El-Sherbiny M, Said E (2015) Amelioration of experimentally induced diabetic nephropathy and renal damage by nilotinib. J Physiol Biochem 71:635–648

    Article  CAS  PubMed  Google Scholar 

  • Engel T, Justo D, Amitai M, Volchek Y, Mayan H (2013) Nilotinib-associated acute pancreatitis. Ann Pharmacother 47:e3

    Article  PubMed  Google Scholar 

  • Gomez-Cambronero LG, Sabater L, Pereda J, Cassinello N, Camps B, Vina J, Sastre J (2002) Role of cytokines and oxidative stress in the pathophysiology of acute pancreatitis: therapeutical implications. Curr Drug Targets Inflamm Allergy 1:393–403

    Article  CAS  PubMed  Google Scholar 

  • Gray KD, Simovic MO, Chapman WC, Blackwell TS, Christman JW, Washington MK, Yull FE, Jaffal N, Jansen ED, Gautman S, Stain SC (2003) Systemic NF-kappa B activation in a transgenic mouse model of acute pancreatitis. J Surg Res 110:310–314

    Article  CAS  PubMed  Google Scholar 

  • Greer SE, Burchard MW (1993) Acute pancreatitis and critical illness: a pancreatic tale of hypoperfusion and inflammation. Chest 136:1413–1419

    Article  Google Scholar 

  • Guesdon JL, Ternynck T, Avrameas S (1979) The use of avidin biotin interaction in immune-enzymatic techniques. J Histochem Cytochem 27:1131–1139

    Article  CAS  PubMed  Google Scholar 

  • Harper SJ, Cheslyn-Curtis S (2011) Acute pancreatitis. Ann Clin Biochem 48:23–37

    Article  CAS  PubMed  Google Scholar 

  • Iyoda M, Shibata T, Hirai Y, Kuno Y, Akizawa T (2011) Nilotinib attenuates renal injury and prolongs survival in chronic kidney disease. J Am Soc Nephrol 22:1486–1496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson JR, Bross P, Cohen M, Rothmann M, Chen G, Zajicek A, Gobburu J, Rahman A, Staten A, Pazdur R (2003) Approval summary: imatinib mesylate capsules for treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Clin Cancer Res 9:1972–1979

    CAS  PubMed  Google Scholar 

  • Jungermann J, Lerch MM, Weidenbach H, Lutz MP, Krüger B, Adler G (1995) Disassembly of rat pancreatic acinar cell cytoskeleton during supramaximal secretagogue stimulation. Am J Phys 268:G328–G338

    CAS  Google Scholar 

  • Kaska M, Pospisilova B, Slizova D (2000) Pathomorphological changes in microcirculation of pancreas during experimental acute pancreatitis. Hepatogastroenterol 47:1570–1574

    CAS  Google Scholar 

  • Kaur J, Sidhu S, Chopra K, Khan MU (2016) Calendula officinalis ameliorates l-arginine-induced acute necrotizing pancreatitis in rats. Pharm Biol 23:1–9

    Google Scholar 

  • Khan AS, Latif SU (2010) Controversies in the etiologies of acute pancreatitis. JOP. 11:545–552

    PubMed  Google Scholar 

  • Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW, Wollman J (1981) Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1:431–435

    Article  CAS  PubMed  Google Scholar 

  • Koksel O, Yildirim C, Cinel L, Tamer L, Ozdulger A, Bastürk M, Degirmenci U, Kanik A, Cinel I (2005) Inhibition of poly (ADP-ribose) polymerase attenuates lung tissue damage after hind limb ischemia-reperfusion in rats. Pharmacol Res 51:453–462

    Article  CAS  PubMed  Google Scholar 

  • Kumar S, Mishra N, Raina D, Saxena S, Kufe D (2003) Abrogation of the cell death response to oxidative stress by the c-abl tyrosine kinase inhibitor STI571. Mol Pharmacol 63(2):276–282

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Yu M, Chen Y, Zhang J (2016) Galunisertib (LY2157299), a transforming growth factor-β receptor I kinase inhibitor, attenuates acute pancreatitis in rats. Braz J Med Biol Res 49:e5388

    CAS  PubMed  PubMed Central  Google Scholar 

  • Luttenberger T, Schmid-Kotsas A, Menke A, Siech M, Beger H, Adler G, Grünert A, Bachem MG (2000) Platelet-derived growth factors stimulate proliferation and extracellular matrix synthesis of pancreatic stellate cells: implications in pathogenesis of pancreas fibrosis. Lab Investig 80:47–55

    Article  CAS  PubMed  Google Scholar 

  • Manley PW, Drueckes P, Fendrich G, Furet P, Liebetanz J, Martiny-Baron G, Mestan J, Trappe J, Wartmann M, Fabbro D (2010) Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochim Biophys Acta 1804:445–453

    Article  CAS  PubMed  Google Scholar 

  • Markowitz SD, Roberts AB (1996) Tumor suppressor activity of the TGF-beta pathway in human cancers. Cytokine Growth Factor Rev 7:93–102

    Article  CAS  PubMed  Google Scholar 

  • Mirmalek SA, Gholamrezaei-Boushehrinejad A, Yavari H, Kardeh B, Parsa Y, Salimi-Tabatabaee SA, Yadollah-Damavandi S, Parsa T, Shahverdi E, Jangholi E (2016) Antioxidant and anti-inflammatory effects of coenzyme Q10 on L-arginine-induced acute pancreatitis in rat. Oxidative Med Cell Longev . doi:10.1155/2016/58184795818479

    Google Scholar 

  • Mizuguchi T, Mukaiya M, Imaizumi H, Kimura Y, Ma-suda Y, Katsuramaki T, Asai Y, Hirata K (2004) Successful management of severe acute pancreatitis with multiple organ failure. Pancreas 28:211–213

    Article  PubMed  Google Scholar 

  • Mizunuma T, Kawamura S, Kishino Y (1984) Effects of injecting excess arginine on rat pancreas. J Nutr 114:467–471

    CAS  PubMed  Google Scholar 

  • Nader MA, Attia GM (2016) Beneficial effects of nilotinib, tyrosine kinase inhibitor on cyclosporine-a induced renal damage in rats. Int Immunopharmacol 33:1–7

    Article  CAS  PubMed  Google Scholar 

  • Nandy D, Mukhopadhyay D (2011) Growth factor mediated signaling in pancreatic pathogenesis. Cancers (Basel) 3:841–871

    Article  CAS  Google Scholar 

  • National Research Council (US) (2011) Committee for the update of the guide for the care and use of laboratory animals. Guide for the care and use of laboratory animals, 8th edition. Washington (DC): National Academies Press (US). 2, Animal care and use program. Available from: http://www.ncbi.nlm.nih.gov/books/NBK54045/

  • Pezzilli R, Corinaldesi R, Morselli-Labate AM (2010) Tyrosine kinase inhibitors and acute pancreatitis. JOP 11:291–293

    PubMed  Google Scholar 

  • Riesle E, Friess H, Wagner M, Uhl W, Baczako K, Gold LI, Korc M, Büchler MW (1997) Increased expression of transforming growth factor beta s after acute oedematous pancreatitis in rats suggests a role in pancreatic repair. Gut 40:73–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Runkel NS, Moody FG, Smith GS, Rodriguez LF, LaRocco MT, Miller TA (1991) The role of the gut in the development of sepsis in acute pancreatitis. J Surg Res 51:18–23

    Article  CAS  PubMed  Google Scholar 

  • Scartozzi M, Bearzi I, Pierantoni C, Mandolesi A, Loupakis F, Zaniboni A, Catalano V, Quadri A, Zorzi F, Berardi R, Biscotti T, Labianca R, Falcone A, Cascinu S (2007) Nuclear factor-kB tumor expression predicts response and survival in irinotecan-refractory metastatic colorectal cancer treated with cetuximab-irinotecan therapy. J Clin Oncol 25:3930–3935

    Article  CAS  PubMed  Google Scholar 

  • Schmidt J, Rattner DW, Lewandrowski K, Compton CC, Mandavilli U, Knoefel WT, Warshaw AL (1992) A better model of acute pancreatitis for evaluating therapy. Ann Surg 215:44–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schreck R, Rieber P, Baeuerle PA (1991) Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 10:2247–2258

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shah V, Lyford G, Gores G, Farrugia G (2004) Nitric oxide in gastrointestinal health and disease. Gastroenterol. 126:903–913

    Article  CAS  Google Scholar 

  • Shaker MA, Zalata KR, Mehal WZ, Shiha GE, Ibrahim TM (2011) Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis. Toxicol Appl Pharmacol 252:165–175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shenkar R, Coulson WF, Abraham E (1994) Anti-transforming growth factor-beta monoclonal antibodies prevent lung injury in hemorrhaged mice. Am J Respir Cell Mol Biol 11:351–357

    Article  CAS  PubMed  Google Scholar 

  • Siegbahn A, Hammacher A, Westermark B, Heldin CH (1990) Differential effects of the various isoforms of platelet-derived growth factor on chemotaxis of fibroblasts, monocytes, and granulocytes. J Clin Invest 85:916–920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smotkin J, Tenner S (2002) Laboratory diagnostic tests in acute pancreatitis. J Clin Gastroenterol 34:459–462

    Article  PubMed  Google Scholar 

  • Steinle AU, Weidenbach H, Wagner M, Adler G, Schmid RM (1999) NF-kappaB/Rel activation in cerulein pancreatitis. Gastroenterol. 116:420–430

    Article  CAS  Google Scholar 

  • Su K, Cuthbertson C, Christophi C (2006) Review of experimental animal models of acute pancreatitis. PHS 8:264–286

    Google Scholar 

  • Takahashi N, Miura M, Kuroki J, Mitani K, Kitabayashi A, Sasaki O, Kimura H, Imai K, Tsukamoto N, Noji H, Kondo T, Motegi M, Kato Y, Mita M, Saito H, Yoshida C, Torimoto Y, Kimura T, Wano Y, Nomura J, Yamamoto S, Mayama K, Honma R, Sugawara T, Sato S, Shinagawa A, Abumiya M, Niioka T, Harigae H, Sawada K (2014) Multicenter phase II clinical trial of nilotinib for patients with imatinib-resistant or intolerant chronic myeloid leukemia from the East Japan CML study group evaluation of molecular response and the efficacy and safety of nilotinib. Biomark Res 2:6

    Article  PubMed  PubMed Central  Google Scholar 

  • Traenckner EB, Wilk S, Baeuerle PA (1994) A proteasome inhibitor prevents activation of NF-kappa B and stabilizes a newly phosphorylated form of I kappa B-alpha that is still bound to NF-kappa B. EMBO J 13:5433–5441

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ueda T, Ho HS, Anderson SE, Takeyama Y (1999) Pancreatitis-induced ascetic fluid and hepatocellular dysfunction in severe acute pancreatitis. J Surg Res 82:305–311

    Article  CAS  PubMed  Google Scholar 

  • Uruñuela A, Sevillano S, de la Mano AM, Manso MA, Orfao A, de Dios I (2002) Time-course of oxygen free radical production in acinar cells during acute pancreatitis induced by pancreatic duct obstruction. Biochim Biophys Acta 1588:159–164

    Article  PubMed  Google Scholar 

  • Viola G, al- Mufti RA, Sohail M, Williamson RC, Mathie RT (2000) Nitric oxide induction in a rat model of selective pancreatic ischemia and reperfusion. Hepato-Gastroenterology 47:1250–1255

    CAS  PubMed  Google Scholar 

  • Vogelmann R, Ruf D, Wagner M, Adler G, Menke A (2001) Effects of fibrogenic mediators on the development of pancreatic fibrosis in a TGF-beta1 transgenic mouse model. Am J Physiol Gastrointest Liver Physiol 280:G164–G172

    CAS  PubMed  Google Scholar 

  • Waldthaler A, Schütte K (2010) Causes and mechanisms in acute pancreatitis. Dig Dis 28:364–372

    Article  CAS  PubMed  Google Scholar 

  • Wallace JL, Miller MJ (2000) Nitric oxide in mucosal defense: a little goes a long way. Gastroenterol 119:512–520

    Article  CAS  Google Scholar 

  • Xie Y, Wang Y, Zong C, Cheng J (2014) Transforming growth factor-beta inhibits heme oxygenase-1 expression in lung fibroblast through nuclear factor-kappa-B-dependent pathway. Pharmacology 93:185–192

    Article  CAS  PubMed  Google Scholar 

  • Yılmaz EE, Bozdağ Z, Ibiloğlu I, Arıkanoğlu Z, Yazgan ÜC, Kaplan I, Gümüş M, Atamanalp SS (2016) Therapeutic effects of ellagic acid on L-arginine induced acute pancreatitis. Acta Cir Bras 31:396–401

    PubMed  Google Scholar 

  • Zhang J, Ning X, Cui W, Bi M, Zhang D, Zhang J (2015) Transforming growth factor (TGF)-beta-induced microRNA-216a promotes acute pancreatitis via Akt and TGF-beta pathway in mice. Dig Dis Sci 60:127–135

    Article  CAS  PubMed  Google Scholar 

  • Zhang XP, Lin Q, Zhou YF (2007a) Progress of study on the relationship between mediators of inflammation and apoptosis in acute pancreatitis. Dig Dis Sci 52:1199–1205

    Article  CAS  PubMed  Google Scholar 

  • Zhang XP, Zhang L, Chen LJ, Cheng QH, Wang JM, Cai W, Shen HP, Cai J (2007b) Influence of dexamethasone on inflammatory mediators and NF kappa B expression in multiple organs of rats with severe acute pancreatitis. World J Gastroenterol 13:548–556

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao X, Dib M, Andersson E, Shi C, Widegren B, Wang X, Andersson R (2005) Alterations of adhesion molecule expression and inflammatory mediators in acute lung injury induced by septic and non-septic challenges. Lung 183:87–100

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Colleague of Pharmacy, Taibah University, Almadinah Almunawwarah, 30001, Saudi Arabia

    Manar A. Nader

  2. Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt

    Manar A. Nader

  3. Pahology Department, Colleague of Medical Health, Taibah University, Almadinah Almunawwarah, 30001, Saudi Arabia

    Heba M. Wagih

  4. Faculty of Medicine, Suez Canal University, Ismailia, Egypt

    Heba M. Wagih

Authors
  1. Manar A. Nader
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Heba M. Wagih
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Manar A. Nader.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nader, M.A., Wagih, H.M. Nilotinib, a tyrosine kinase inhibitor exhibits protection against acute pancreatitis-induced lung and liver damage in rats. Naunyn-Schmiedeberg's Arch Pharmacol 390, 291–300 (2017). https://doi.org/10.1007/s00210-016-1327-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-016-1327-2

Keywords

Search

Navigation