Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Typ-2-Diabetes und Adipositas Klimawandel und Gesundheit Neues aus dem Markt Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende Patientenratgeber
Erweiterte Suche
Anmelden
nach oben
Cardiovascular Toxicology
Erschienen in:

06.11.2019

Protective Effect of RIVA Against Sunitinib-Induced Cardiotoxicity by Inhibiting Oxidative Stress-Mediated Inflammation: Probable Role of TGF-β and Smad Signaling

verfasst von: Faisal Imam, Naif Obaid Al-Harbi, Mohammad Rashid Khan, Wajhul Qamar, Metab Alharbi, Ali A. Alshamrani, Hussain N. Alhamami, Nasser Bader Alsaleh, Khalid Saad Alharbi

Erschienen in: Cardiovascular Toxicology | Ausgabe 3/2020

Einloggen, um Zugang zu erhalten

Abstract

Sunitinib (SUN) is an oral tyrosine kinase inhibitor approved in 2006 as a first-line treatment for metastatic renal cell cancer. However, weak selectivity to kinase receptors and cardiotoxicity have limited the use of sunitinib. Rivaroxaban (RIVA) is a Factor Xa inhibitor with cardioprotective action. It inhibits atherosclerosis and numerous inflammatory cascades. The present study was designed to investigate the cardioprotective effects of RIVA in sunitinib-induced cardiotoxicity. Thirty male Wistar rats were divided into five groups. Group 1 was the normal control (control). Group 2 was administered i.p. SUN 25 mg kg−1 thrice weekly for 3 weeks. Groups 3 and 4 received the same treatment as Group 2 followed by the administration of RIVA 5 mg kg−1 day−1 and 10 mg kg−1 day−1, respectively, for 3 weeks. Group 5 received only 10 mg kg−1 day−1 RIVA for 3 weeks. Serum levels of Ca2+, Mg2+, Fe3+/Fe2+, lipid profiles, and cardiac enzymes were measured. Cardiac tissues were isolated for the measurements of oxidant/antioxidant balance gene and protein expressions. Relative to the controls, the administration of SUN significantly altered serum levels of (Ca2+, Mg2+, Fe3+/Fe2+, lipid profiles, and cardiac enzymes), intracellular antioxidant enzymes, and the expression levels of the genes encoding certain proteins. RIVA treatment significantly restored these parameters to near-normal levels. RIVA treatment significantly mitigated SUN-induced cardiac injuries by restoring antioxidant enzyme levels and attenuating the proinflammatory cascades resulting from SUN-induced cardiac injuries.
Literatur
1.
Le Tourneau, C., Raymond, E., & Faivre, S. (2007). Sunitinib: A novel tyrosine kinase inhibitor. A brief review of its therapeutic potential in the treatment of renal carcinoma and gastrointestinal stromal tumors (GIST). Therapeutics and Clinical Risk Management,3, 341.PubMedPubMedCentral
2.
Awazu, Y., Mizutani, A., Nagase, Y., Iwata, H., Oguro, Y., Miki, H., et al. (2012). A novel pyrrolo [3,2-d] pyrimidine derivative, as a vascular endothelial growth factor receptor and platelet-derived growth factor receptor tyrosine kinase inhibitor, shows potent antitumor activity by suppression of tumor angiogenesis. Cancer Science,103(5), 939–944.PubMedPubMedCentral
3.
Force, T., Krause, D. S., & Van Etten, R. A. (2007). Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nature Reviews Cancer,7, 332–344.PubMed
4.
Chu, T. F., Rupnick, M. A., Kerkela, R., Dallabrida, S. M., Zurakowski, D., Nguyen, L., et al. (2007). Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. The Lancet,370, 2011–2019.
5.
Kerkela, R., Grazette, L., Yacobi, R., Iliescu, C., Patten, R., Beahm, C., et al. (2006). Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature Medicine,12, 908–916.PubMed
6.
7.
Vimalesvaran, K., Dockrill, S. J., & Gorog, D. A. (2018). Role of rivaroxaban in the management of atrial fibrillation: Insights from clinical practice. Vascular Health and Risk Management,14, 13–21.PubMedPubMedCentral
8.
Sharma, A., Garg, A., Borer, J. S., Krishnamoorthy, P., Garg, J., Lavie, C. J., et al. (2014). Role of oral factor Xa inhibitors after acute coronary syndrome. Cardiology,129(4), 224–232.PubMed
9.
Hara, T., Fukuda, D., Tanaka, K., Higashikuni, Y., Hirata, Y., Nishimoto, S., et al. (2015). Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice. Atherosclerosis,242(2), 639–646.PubMed
10.
Sparkenbaugh, E. M., Chantrathammachart, P., Mickelson, J., van Ryn, J., Hebbel, R. P., Monroe, D. M., et al. (2014). Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease. Blood,123(11), 1747–1756.PubMedPubMedCentral
11.
Bukowska, A., Zacharias, I., Weinert, S., Skopp, K., Hartmann, C., Huth, C., et al. (2013). Coagulation factor Xa induces an inflammatory signalling by activation of protease activated receptors in human atrial tissue. European Journal of Pharmacology,718(13), 114–123.PubMed
12.
Ishibashi, Y., Matsui, T., Ueda, S., Fukami, K., & Yamagishi, S. (2014). Advanced glycation end products potentiate citrated plasma evoked oxidative and inflammatory reactions in endothelial cells by upregulating protease activated receptor 1 expression. Cardiovascular Diabetology,13, 60.PubMedPubMedCentral
13.
Iba, T., Aihara, K., Yamada, A., Nagayama, M., Tabe, Y., & Ohsaka, A. (2014). Rivaroxaban attenuates leukocyte adhesion in the microvasculature and thrombus formation in an experimental mouse model of type 2 diabetes Mellitus. Thrombosis Research,133(2), 276–280.PubMed
14.
Dammacco, F., Vacca, A., Procaccio, P., Ria, R., Marech, I., & Racanelli, V. (2013). Cancer related coagulopathy (Trousseau’s syndrome): Review of the literature and experience of a single center of internal medicine. International Journal of Clinical and Experimental Medicine,13(2), 85–97.
15.
Blasi, E., Heyen, J., Patyna, S., Hemkens, M., Ramirez, D., John-Baptiste, A., et al. (2012). Sunitinib, a receptor tyrosine kinase inhibitor, increases blood pressure in rats without associated changes in cardiac structure and function. Cardiovascular Therapeutics,30(5), 287–294.PubMed
16.
Yang, Y., Li, N., Chen, T., Zhang, C., Liu, L., Qi, Y., et al. (2019). Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway. Pharmaceutical Biology,57(1), 625–631.PubMedPubMedCentral
17.
Kerkela, R., Woulfe, K. C., Durand, J. B., Vagnozzi, R., Kramer, D., Chu, T. F., et al. (2009). Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. Clinical and Translational Science,2(1), 15–25.PubMedPubMedCentral
18.
Fujiwara, Y., Ando, H., Ushijima, K., Horiguchi, M., Yamashita, C., & Fujimura, A. (2017). Dosing-time-dependent effect of rivaroxaban on coagulation activity in rats. Journal of Pharmacological Sciences,134(4), 234–238.PubMed
19.
Perzborn, Elisabeth, Hirth-Dietrich, Claudia, Fischer, Elke, Groth, Martin, Hartmann, Elke, & Sperlich-Wulf, Kerstin. (2007). Rivaroxaban has protective effects in a model of disseminated intravascular coagulation (DIC) in rats. Blood,110, 935.
20.
Imam, F., Al-Harbi, N. O., Al-Harbi, M. M., et al. (2015). Diosmin downregulates the expression of T cell receptors, pro-inflammatory cytokines and NF-kB activation against LPS-induced acute lung injury in mice. Pharmacological Research,102, 1–11.PubMed
21.
Imam, F., Al-Harbi, N. O., Al-Harbia, M. M., Korashy, H. M., Ansari, M. A., Sayed-Ahmed, M. M., et al. (2017). Rutin attenuates carfilzomib-induced cardiotoxicity through inhibition of NF-kappaB, hypertrophic gene expression and oxidative stress. Cardiovascular Toxicology,17(1), 58–66.PubMed
22.
Sedlak, J., & Lindsay, R. H. (1968). Estimation of total, protein bound and non-protein bound sulfhydryl groups in tissue with Ellman’s reagent. Analytical Biochemistry,25, 192–205.PubMed
23.
Carlberg, I., & Mannervik, B. (1985). Glutathione reductase. Methods in Enzymology, 113, 484–490.PubMed
24.
Al-Harbi, N. O. (2016). Carfilzomib-induced cardiotoxicity mitigated by dexrazoxane through inhibition of hypertrophic gene expression and oxidative stress in rats. Toxicology Mechanisms and Methods,26(3), 189–195.PubMed
25.
Ahmad, S. F., Zoheir, K. M., Ansari, M. A., et al. (2015). Histamine 4 receptor promotes expression of costimulatory B7.1/B7.2 molecules, CD28 signaling and cytokine production in stress induced immune responses. Journal of Neuroimmunology,15(289), 30–42.
26.
Barakat, M. M., El-Kadi, A. O., & du Souich, P. (2001). L-NAME prevents in vivo the inactivation but not the down-regulation of hepatic cytochrome P450 caused by an acute inflammatory reaction. Life Sciences,69, 1559–1571.PubMed
27.
Lowry, O. H., Rosebrough, N. J., Farr, A. L., & Randall, R. J. (1951). Protein with the Folin phenol reagent. Journal of Biological Chemistry,193(1), 265–275.
28.
Abrams, T. J., Lee, J. B., Murray, L. J., Pryer, N. K., & Cherrington, J. M. (2003). SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Molecular Cancer Therapeutics,2, 471–478.PubMed
29.
Mendel, D. B., Laird, A. D., Xin, X., et al. (2003). In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clinical Cancer Research,9, 327–337.PubMed
30.
Le Tourneau, Christophe, Raymond, Eric, & Faivre, Sandrine. (2007). Sunitinib: a novel tyrosine kinase inhibitor: A brief review of its therapeutic potential in the treatment of renal carcinoma and gastrointestinal stromal tumors (GIST). Therapeutics and Clinical Risk Management,3(2), 341–348.PubMedPubMedCentral
31.
Sandhu, Hardip, Cooper, Samantha, Hussain, Afthab, Mee, Christopher, & Maddock, Helen. (2017). Attenuation of Sunitinib-induced cardiotoxicity through the A3 adenosine receptor activation. European Journal of Pharmacology,814, 95–105.PubMed
32.
Uraizee, I., Cheng, S., & Moslehi, J. (2011). Reversible cardiomyopathy associated with sunitinib and sorafenib. New England Journal of Medicine,365, 1649–1650.
33.
Mooney, L., Skinner, M., Coker, S., & Currie, S. (2015). Effects of acute and chronic sunitinib treatment on cardiac function and calcium/calmodulin-dependent protein kinase II. British Journal of Pharmacology,172, 4342–4354.PubMedPubMedCentral
34.
35.
Georgieva, E., Ivanova, D., Zhelev, Z., Bakalova, R., Gulubova, M., & Aoki, I. (2017). Mitochondrial dysfunction and redox imbalance as a diagnostic marker of “Free Radical Diseases”. Anticancer Research,37(10), 5373–5381.PubMed
36.
37.
Ishibashi, Y., Matsui, T., Fukami, K., Ueda, S., Okuda, S., & Yamagishi, S. (2015). Rivaroxaban inhibits oxidative and inflammatory reactions in advanced glycation end product-exposed tubular cells by blocking thrombin/protease-activated receptor-2 system. Thrombosis Research,135, 770–773.PubMed
38.
Balasubramaniyan, V., & Nalini, N. (2007). Effect of leptin on peroxidation and antioxidant defense in ethanol-supplemented Mus musculus heart. Fundamental & Clinical Pharmacology,21, 245–253.
39.
Saravanan, R., & Pugalendi, V. (2006). Impact of ursolic acid on chronic ethanol-induced oxidative stress in the rat heart. Pharmacological Reports,58, 41–47.PubMed
40.
Subbaiah, G. V., Mallikarjuna, K., Shanmugam, B., Ravi, S., Taj, P. U., & Reddy, K. S. (2017). Ginger treatment ameliorates alcohol-induced myocardial damage by suppression of hyperlipidemia and cardiac biomarkers in rats. Pharmacognosy Magazine,13(Suppl 1), S69–S75.PubMedPubMedCentral
41.
Huang, Q., Zhou, C., Chen, X., Dong, B., Chen, S., Zhang, N., et al. (2015). Prodrug AST-003 improves the therapeutic index of the multi-targeted tyrosine kinase inhibitor sunitinib. PLoS ONE,10(10), e0141395.PubMedPubMedCentral
42.
Janet, K., Lighthouse, C., & Eric, M. (2016). Small. Transcriptional control of cardiac fibroblast plasticity. Journal of Molecular and Cellular Cardiology,91, 52–60.
43.
Bujak, M., & Frangogiannis, N. G. (2007). The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovascular Research,74(2), 184–195.PubMed
44.
Creemers, E. E., & Pinto, Y. M. (2011). Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart. Cardiovascular Research,89, 265–272.PubMed
45.
Massague, J., Seoane, J., & Wotton, D. (2008). Smad transcription factors. Genes & Development,19(23), 2783–2810.
46.
Nakao, A., Afrakhte, M., Morén, A., Nakayama, T., Christian, J. L., Heuchel, R., et al. (1997). Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature,389(6651), 631–635.PubMed
47.
Dobaczewski, M., Bujak, M., Li, N., Gonzalez-Quesada, C., Mendoza, L. H., Wang, X. F., et al. (2010). Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction. Circulation Research,107(3), 418–428.PubMedPubMedCentral
48.
Biernacka, A., Cavalera, M., Wang, J., Russo, I., Shinde, A., Kong, P., et al. (2015). Smad3 signaling promotes fibrosis while preserving cardiac and aortic geometry in obese diabetic mice. Circulation: Heart Failure,8(4), 788–798.
49.
Massagué, J. (1998). TGF-β signal transduction. Annual Review of Biochemistry,67, 753–791.PubMed
50.
Yuan, S. M., & Jing, H. (2010). Cardiac pathologies in relation to Smad-dependent pathways. Interactive CardioVascular and Thoracic Surgery,11, 455–460.PubMed
51.
Barnette, D. N., Hulin, A., Ahmed, A. S., Colige, A. C., Azhar, M., & Lincoln, J. (2013). TGF-β-Smad and MAPK signaling mediate scleraxis and proteoglycan expression in heart valves. Journal of Molecular and Cellular Cardiology,65, 137–146.PubMed
52.
Rodríguez-Vita, J., Sánchez-López, E., Esteban, V., Rupérez, M., Egido, J., & Ruiz-Ortega, M. (2005). Angiotensin II activates the Smad pathway in vascular smooth muscle cells by a transforming growth factor-β–independent mechanism. Circulation,111, 2509–2517.PubMed
53.
Isono, M., Chen, S., Won Hong, S., Iglesias-de, Carmen, la Cruz, M., & Ziyadeh, F. N. (2002). Smad pathway is activated in the diabetic mouse kidney and Smad3 mediates TGF-β-induced fibronectin in mesangial cells. Biochemical and Biophysical Research Communications,296, 1356–1365.PubMed
54.
Chen, Y. G., Hata, A., Lo, R. S., Wotton, D., Shi, Y., Pavletich, N., et al. (1998). Determinants of specificity in TGF-β signal transduction. Genes & Development,12, 2144–2152.
55.
Akhurst, R. J., & Hata, A. (2012). Targeting the TGF-β signalling pathway in disease. Nature Reviews Drug Discovery,11, 790–811.PubMedPubMedCentral
56.
Bujak, M., & Frangogiannis, N. G. (2007). The role of TGF-β signaling in myocardial infarction and cardiac remodeling. Cardiovascular Research,74, 184–195.PubMed
57.
Derynck, R., & Zhang, Y. E. (2003). Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature,425, 577–584.PubMed
58.
Massagué, J., & Chen, Y. G. (2000). Controlling TGF-β signaling. Genes & Development,14(6), 627–644.
59.
Jumeau, C., Rupin, A., Chieng-Yane, P., Mougenot, N., Zahr, N., David-Dufilho, M., et al. (2016). Direct thrombin inhibitors prevent left atrial remodeling associated with heart failure in rats. JACC: Basic to Translational Science,1(5), 328–339.PubMedPubMedCentral
60.
Korashy, H. M., Al-Suwayeh, H. A., Maayah, Z. H., Ansari, M. A., Ahmad, S. F., & Bakheet, S. A. (2015). Mitogen-activated protein kinases pathways mediate the sunitinib-induced hypertrophy in rat cardiomyocyte H9c2 cells. Cardiovascular Toxicology,15(1), 41–51.PubMed
Metadaten
Titel
Protective Effect of RIVA Against Sunitinib-Induced Cardiotoxicity by Inhibiting Oxidative Stress-Mediated Inflammation: Probable Role of TGF-β and Smad Signaling
verfasst von
Faisal Imam
Naif Obaid Al-Harbi
Mohammad Rashid Khan
Wajhul Qamar
Metab Alharbi
Ali A. Alshamrani
Hussain N. Alhamami
Nasser Bader Alsaleh
Khalid Saad Alharbi
Publikationsdatum
06.11.2019
Verlag
Springer US
Erschienen in
Cardiovascular Toxicology / Ausgabe 3/2020
Print ISSN: 1530-7905
Elektronische ISSN: 1559-0259
DOI
https://doi.org/10.1007/s12012-019-09551-8

Weitere Artikel der Ausgabe 3/2020

The Role of Topoisomerase IIβ in the Mechanisms of Action of the Doxorubicin Cardioprotective Agent Dexrazoxane

The Effects of Neuropeptide Y Overexpression on the Mouse Model of Doxorubicin-Induced Cardiotoxicity

  • Open Access

Assessment of Pregabalin-Induced Cardiotoxicity in Rats: Mechanistic Role of Angiotensin 1–7

Late-life Cardiac Injury in Rats following Early Life Exposure to Lead: Reversal Effect of Nutrient Metal Mixture

Impact of Arterial Hypertension on Doxorubicin-Based Chemotherapy-Induced Subclinical Cardiac Damage in Breast Cancer Patients

Effects of Hyperbaric Oxygen Therapy on Acute Myocardial Infarction Following Carbon Monoxide Poisoning