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Rutin Attenuates Carfilzomib-Induced Cardiotoxicity Through Inhibition of NF-κB, Hypertrophic Gene Expression and Oxidative Stress

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Abstract

Carfilzomib is a proteasome inhibitor, commonly used in multiple myeloma, but its clinical use may be limited due to cardiotoxicity. This study was aimed to evaluate the influence of rutin in carfilzomib-induced cardiotoxicity in rats. Wistar albino male rats weighing 200–250 g (approximately 10 weeks old) were taken for this study. Animals were divided into four groups of six animals each. Group 1 served as normal control (NC), received normal saline; group 2 animals received carfilzomib (dissolved in 1 % DMSO) alone; group 3 animals received rutin (20 mg/kg) + carfilzomib; and group 4 animals received rutin (40 mg/kg) + carfilzomib. Hematological changes, biochemical changes, oxidative stress, hypertrophic gene expression, apoptotic gene expression, NFκB and IκB-α protein expression and histopathological evaluation were done to confirm the finding of carfilzomib-induced cardiotoxicity. Treatment with rutin decreased the carfilzomib-induced changes in cardiac enzymes such as lactate dehydrogenase, creatine kinase (CK) and CK-MB. For the assessment of cardiotoxicity, we further evaluated cardiac hypertrophic gene and apoptotic gene expression such as α-MHC, β-MHC and BNP and NF-κB and p53 gene expression, respectively, using RT-PCR. Western blot analysis showed that rutin treatment prevented the activation of NF-κB by increasing the expression of IκB-α. Rutin also attenuated the effects of carfilzomib on oxidant-antioxidant including malondialdehyde and reduced glutathione. Histopathological study clearly confirmed that rutin attenuated carfilzomib-induced cardiotoxicity in rats.

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References

  1. Demo, S. D., Kirk, C. J., Aujay, M. A., Buchholz, T. J., Dajee, M., Ho, M. N., et al. (2007). Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Research, 67, 6383–6391.

    Article  CAS  PubMed  Google Scholar 

  2. Hajek, R., Bryce, R., Ro, S., Klencke, B., & Ludwig, H. (2012). Design and rationale of FOCUS (PX-171-011): A randomized, open-label, phase 3 study of carfilzomib versus best supportive care regimen in patients with relapsed and refractory multiple myeloma (R/R MM). BMC Cancer, 12, 415–521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Herndon, T. M., Deisseroth, A., Kaminskas, E., Kane, R. C., Koti, K. M., Rothmann, M. D., et al. (2013). Food and drug administration approval: Carfilzomib for the treatment of multiple myeloma. Clinical Cancer Research, 19(17), 4559–4563.

    Article  CAS  PubMed  Google Scholar 

  4. Fuchs, O., Provaznikova, D., Marinov, I., Kuzelova, K., & Spicka, I. (2009). Antiproliferative and proapoptotic effects of proteasome inhibitors and their combination with histone deacetylase inhibitors on leukemia cells. Cardiovascular & Hematological Disorders: Drug Targets, 9, 62–77.

    Article  CAS  Google Scholar 

  5. Khan, R. Z., & Badros, A. (2012). Role of carfilzomib in the treatment of multiple myeloma. Expert Review of Hematology, 5, 361–372.

    Article  CAS  PubMed  Google Scholar 

  6. Vij, R., Siegel, D. S., Jagannath, S., Jakubowiak, A. J., Stewart, A. K., McDonagh, K., et al. (2012). An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. British Journal of Haematology, 158, 739–748.

    Article  CAS  PubMed  Google Scholar 

  7. Chari, A., & Hajje, D. (2014). Case series discussion of cardiac and vascular events following carfilzomib treatment: Possible mechanism, screening, and monitoring. BMC Cancer, 14, 915–923.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Siegel, D., Martin, T., Nooka, A., Harvey, R. D., Vij, R., Niesvizky, R., et al. (2013). Integrated safety profile of single-agent carfilzomib: Experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica, 98, 1753–1761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Siegel, D. S., Martin, T., Wang, M., Vij, R., Jakubowiak, A. J., Lonial, S., et al. (2012). A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood, 120(14), 2817–2825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Force, W. I. T. (1980). Report of the WHO/ISFC task force on the definition and classification of cardiomyopathies. British Heart Journal 44(6), 672–673.

  11. Abelmann, W. H. (1984). Classification and natural history of primary myocardial disease. Progress in Cardiovascular Diseases, 27(2), 73–94.

    Article  CAS  PubMed  Google Scholar 

  12. Richardson, P., McKenna, W., Bristow, M., Maisch, B., Mautner, B., O’Connell, J., et al. (1996). Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation, 93(5), 841–842.

    Article  CAS  PubMed  Google Scholar 

  13. Shanmugarajan, T. S., Arunsunder, M., Somasundaram, I., Krishnakumar, E., Sivaraman, D., & Ravichandiran, V. (2008). Protective effect of Ficus hispida Linn. on cyclophosphamide provoked oxidative myocardial injury in rat model. International Journal of Pharmacology, 4(2), 78–87.

    Article  Google Scholar 

  14. Repetto, A., Dal Bello, B., Pasotti, M., Agozzino, M., Vigano, M., Klersy, C., et al. (2005). Coronary atherosclerosis in end-stage idiopathic dilated cardiomyopathy: An innocent bystander? European Heart Journal, 26(15), 1519–1527.

    Article  PubMed  Google Scholar 

  15. Barry, S. P., Davidson, S. M., & Townsend, P. A. (2008). Molecular regulation of cardiac hypertrophy. International Journal of Biochemistry & Cell Biology, 40(10), 2023–2039.

    Article  CAS  Google Scholar 

  16. Miyata, S., Minobe, W., Bristow, M. R., & Leinwand, L. A. (2000). Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circulation Research, 86(4), 386–390.

    Article  CAS  PubMed  Google Scholar 

  17. Reiser, P. J., Portman, M. A., Ning, X. H., & Schomisch Moravec, C. (2001). Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles. American Journal of Physiology Heart and Circulatory Physiology, 280(4), H1814–H1820.

    CAS  PubMed  Google Scholar 

  18. Lee, H., Son, C. B., Shin, S. H., & Kim, Y. S. (2008). Clinical correction between brain natriuretic peptide and anthracycline-induced cardiotoxicity. Cancer Research and Treatment, 40, 121–126.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cowie, M. R., Jourdain, P., Maisel, A., Dahlstrom, U., Follath, F., Isnard, R., et al. (2003). Clinical applications of B-type natriuretic peptide (BNP) testing. European Heart Journal, 24(19), 1710–1718.

    Article  CAS  PubMed  Google Scholar 

  20. Oeckinghaus, A., & Ghosh, S. (2009). The NF-κB family of transcription factors and its regulation. Cold Spring Harbor Perspectives in Biology, 1(4), 1–14.

    Article  Google Scholar 

  21. Liu, S. F., & Malik, A. B. (2006). NF-kappa B activation as a pathological mechanism of septic shock and inflammation. American Journal of Physiology. Lung Cellular and Molecular Physiology, 290(4), L622–L645.

    Article  CAS  PubMed  Google Scholar 

  22. Brandes, R. P., & Kreuzer, J. (2005). Vascular NADPH oxidases: Molecular mechanisms of activation. Cardiovascular Research, 65, 16–27.

    Article  CAS  PubMed  Google Scholar 

  23. Konukoglu, D., Serin, O., Kemerli, D. G., Serin, E., Hayirhoglu, A., & Oner, B. (1998). A study on the carotid artery intima-media thickness and its association with lipid peroxidation. Clinica Chimica Acta, 277, 91–98.

    Article  CAS  Google Scholar 

  24. Inoue, M. (2011). Protective mechanisms against reactive oxygen species. In I. M. Arias, J. L. Boyer, N. Fausto, W. B. Jokoby, D. A. Schachter, & D. A. Shafritz (Eds.), The liver: Biology and pathobiology (5th ed., pp. 443–459). New York: Raven Press.

    Google Scholar 

  25. Wu, G., Fang, Y. Z., Yang, S., Lupton, J. R., & Turner, N. D. (2004). Glutathione metabolism and its implications for health. Journal of Nutrition, 134, 489–492.

    CAS  PubMed  Google Scholar 

  26. Zindenberg, C. S., Olin, K. L., & Villarweva, J. (1991). Ethanol induced changes in hepatic free radical defense mechanisms and fatty acid composition in the miniature pig. Hepatology, 13, 1185–1192.

    Article  Google Scholar 

  27. Altinterim, B. (2014). Citrus, rutin and on their vein permeability effects. RJAEM, 3(2), 80–81.

    Google Scholar 

  28. Heather, S., Demrow, B. S., Peter, R., Slane, B. S., & John, D. F. (1995). Administration of wine and grape juice inhibits in vivo platelet activity and thrombosis in stenosed canine coronary arteries. American Heart Association, 91, 1182–1188.

    Google Scholar 

  29. Benavente-Garcia, O., & Castillo, J. (2008). Update on uses and properties of citrus flavonoids: New findings in anticancer, cardiovascular, and antiinflammatory activity. Journal of Agriculture and Food Chemistry, 56(15), 6185–6205.

    Article  CAS  Google Scholar 

  30. Panchal, S. K., Poudyal, H., Arumugam, T. V., & Brown, L. (2011). Rutin attenuates metabolic changes, nonalcoholic steatohepatitis, and cardiovascular remodeling in high-carbohydrate, high-fat diet-fed rats. Journal of Nutrition, 141, 1062–1069.

    Article  CAS  PubMed  Google Scholar 

  31. Panchal, S. K., Poudyal, H., & Brown, L. (2012). Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in DIET-induced metabolic syndrome in rats. Journal of Nutrition, 142(6), 1026–1032.

    Article  CAS  PubMed  Google Scholar 

  32. Yang, J., Wang, Z., Fang, Y., Jiang, J., Zhao, F., Wong, H., et al. (2011). Pharmacokinetics, pharmacodynamics, metabolism, distribution, and excretion of carfilzomib in rats. Drug Metabolism and Disposition, 39, 1873–1882.

    Article  CAS  PubMed  Google Scholar 

  33. Imam, F., Al-Harbi, N. O., Al-Harbi, M. M., Ansari, M. A., Zoheir, K. M., Iqbal, M., et al. (2015). Diosmin downregulates the expression of T cell receptors, pro-inflammatory cytokines and NF-κB activation against LPS-induced acute lung injury in mice. Pharmacological Research, 102, 1–11.

    Article  CAS  PubMed  Google Scholar 

  34. Lowry, O. H., Rosebrough, N. J., Farr, A. L., & Randall, R. J. (1951). Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry, 193, 265–275.

    CAS  PubMed  Google Scholar 

  35. Korashy, H. M., & El-Kadi, A. O. (2004). Differential effects of mercury, lead and copper on the constitutive and inducible expression of aryl hydrocarbon receptor (AHR)-regulated genes in cultured hepatoma Hepa 1c1c7 cells. Toxicology, 201(1–3), 153–172.

    Article  CAS  PubMed  Google Scholar 

  36. Ohkawa, H., Ohishi, N., & Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry, 95, 351–358.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

  38. Al-Harbi, N. O., Imam, F., Nadeem, A., Al-Harbi, M. M., Iqbal, M., Rahman, S., et al. (2014). Protection against tacrolimus-induced cardiotoxicity in rats by olmesartan and aliskiren. Toxicology Mechanisms and Methods, 24(9), 697–702.

    Article  CAS  PubMed  Google Scholar 

  39. Singal, P. K., & Iliskovic, N. (1998). Doxorubicin-induced cardiomyopathy. New England Journal of Medicine, 339, 900–905.

    Article  CAS  PubMed  Google Scholar 

  40. Yeh, E. T. H., Tong, A. T., Lenihan, D. J., Yusuf, S. W., Swafford, J., Champion, C., et al. (2004). Review: Current perspective: Cardiovascular complications of cancer therapy diagnosis, pathogenesis, and management. Circulation, 109, 3122–3131.

    Article  PubMed  Google Scholar 

  41. Al-Shabanah, O., Aleisa, A. M., Hafez, M. M., Al-Rejaie, S. S., Al-Yahya, A. A., Bakheet, S. A., et al. (2012). Desferrioxamine attenuates doxorubicin-induced acute cardiotoxicity through TFG-β/Smad p53 pathway in rat model. Oxidative Medicine and Cellular Longevity, 2012, 1–7.

    Article  Google Scholar 

  42. Piura, B., & Rabinovich, A. (2005). Doxorubicin and ifosfamidemesna in advanced and recurrent uterine sarcomasl. European Journal of Gynaecological Oncology, 26(3), 275–278.

    CAS  PubMed  Google Scholar 

  43. Al-Shabanah, O., Mansour, M., El-Kashef, H., & Al-Bekairi, A. (1998). Captopril ameliorates myocardial and hematological toxicities induced by adriamycin. Biochemistry and Molecular Biology International, 45, 419–427.

    CAS  PubMed  Google Scholar 

  44. el-Missiry, M. A., Othman, A. I., Amer, M. A., & Abdel-Aziz, M. A. (2001). Attenuation of the acute adriamycin-induced cardiac and hepatic oxidative toxicity by N-(2-mercaptopropionyl) glycine in rats. Free Radical Research, 35, 575–581.

    Article  CAS  PubMed  Google Scholar 

  45. Rashikh, A., Najmi, A. K., Akhtar, M., Mahmood, D., Pillai, K. K., & Ahmad, S. J. (2011). Protective effects of aliskiren in doxorubicin-induced acute cardiomyopathy in rats. Human and Experimental Toxicology, 30, 102–109.

    Article  CAS  PubMed  Google Scholar 

  46. Yagmurca, M., Fadillioglu, E., Erdogan, H., Ucar, M., Sogut, S., & Irmak, M. K. (2003). Erdosteine prevents doxorubicin-induced cardiotoxicity in rats. Pharmacological Research, 48, 377–382.

    Article  CAS  PubMed  Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

  48. Maayah, Z. H., Ansari, M. A., El Gendy, M. A., Al-Arifi, M. N., & Korashy, H. M. (2014). Development of cardiac hypertrophy by sunitinib in vivo and in vitro rat cardiomyocytes is influenced by the aryl hydrocarbon receptor signaling pathway. Archives of Toxicology, 88(3), 725–738.

    CAS  PubMed  Google Scholar 

  49. Das, B., Young, D., Vasanji, A., Gupta, S., Sarkar, S., & Sen, S. (2010). Influence of p53 in the transition of myotrophin-induced cardiac hypertrophy to heart failure. Cardiovascular Research, 87(3), 524–534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Surget, S., Khoury, M. P., & Bourdon, J. C. (2013). Uncovering the role of p53 splice variants in human malignancy: A clinical perspective. OncoTargets and Therapy, 7, 57–68.

    PubMed  PubMed Central  Google Scholar 

  51. Cusack, J. C., Liu, R., & Baldwin, A. S. (1999). NF-kappa B and chemoresistance: Potentiation of cancer drugs via inhibition of NF-kappa B. Drug Resistance Updates, 2(4), 271–273.

    Article  CAS  PubMed  Google Scholar 

  52. Tergaonkar, V., Pando, M., Vafa, O., Wahl, G., & Verma, I. (2002). p53 stabilization is decreased upon NFkappaB activation: A role for NFkappaB in acquisition of resistance to chemotherapy. Cancer Cell, 1(5), 493–503.

    Article  CAS  PubMed  Google Scholar 

  53. Perkins, N. D., & Gilmore, T. D. (2006). Good cop, bad cop: the different faces of NF-kappaB. Cell Death and Differentiation, 13(5), 759–772.

    Article  CAS  PubMed  Google Scholar 

  54. Ahmad, S. F., Attia, S. M., Bakheet, S. A., Zoheir, K. M. A., Ansari, M. A., Korashy, H. M., et al. (2015). Naringin attenuates the development of carrageenan-induced acute lung inflammation through inhibition of NF-κb, STAT3 and pro-inflammatory mediators and enhancement of IκBα and anti-inflammatory cytokines. Inflammation, 38(2), 846–857.

    Article  CAS  PubMed  Google Scholar 

  55. Ibrahim, M. A., Ashour, O. M., Ibrahim, Y. F., El-Bitar, H. I., Gomaa, W., & Abdel-Rahim, S. R. (2009). Angiotensin-converting enzyme inhibition and angiotensin AT(1)-receptor antagonism equally improve doxorubicin-induced cardiotoxicity and nephrotoxicity. Pharmacological Research, 60, 373–381.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The present work was funded by King Saud University, Deanship of Scientific Research, College of Pharmacy (Project No. RGP-VPP-305). The authors acknowledge the Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University for its facilities.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia

    Faisal Imam, Naif O. Al-Harbi, Mohammed M. Al-Harbia, Hesham M. Korashy, Mushtaq Ahmad Ansari, Mohamed M. Sayed-Ahmed & Mahmoud N. Nagi

  2. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia

    Muzaffar Iqbal

  3. Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia

    Md. Khalid Anwer

  4. Glocal School of Pharmacy, Glocal University, Saharanpur, India

    Imran Kazmi & Muhammad Afzal

  5. Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Madinah, Kingdom of Saudi Arabia

    Saleh Bahashwan

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  1. Faisal Imam
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  2. Naif O. Al-Harbi
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  3. Mohammed M. Al-Harbia
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Correspondence to Faisal Imam.

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Imam, F., Al-Harbi, N.O., Al-Harbia, M.M. et al. Rutin Attenuates Carfilzomib-Induced Cardiotoxicity Through Inhibition of NF-κB, Hypertrophic Gene Expression and Oxidative Stress. Cardiovasc Toxicol 17, 58–66 (2017). https://doi.org/10.1007/s12012-015-9356-5

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