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3 Biotech

, 8:399 | Cite as

Curcumin-mediated effects on anti-diabetic drug-induced cardiotoxicity

  • Aditi Jain
  • Vibha Rani
Original Article

Abstract

The present study was designed to compare the cardiotoxicity of two very commonly used anti-diabetic drugs namely pioglitazone (Pio) and metformin (Met); and to study the effects of curcumin (Curc) against these drug-induced cardiotoxicity. Curc, being an anti-oxidant molecule and having cardio-protective potential, can have promising synergistic effects in reducing the cardiac stress induced by anti-diabetic therapies. Various dose and time-dependent cell viability and oxidative stress assays were conducted to study cardiotoxic side-effects and Curc-mediated effects in cardiomyoblasts. Effects of Curc were also studied in hyperglycaemia induced cardiac stress in the presence of drugs. Quantitative assays for cell growth, reactive oxygen species (ROS) generation, lipid peroxidation and mitochondrial permeability followed by anti-oxidant enzymes and caspases activity assays were done to study the mechanism of action of the induced cardiotoxicity. Significant dose and time mediated deleterious effects of Pio and Met were witnessed. Oxidative stress studies showed a remarkable increase in ROS with increasing dose of anti-diabetic drugs. Increased caspase activity and altered mitochondrial integrity were also witnessed in presence of Met and Pio in cardiomyoblasts. These alterations were found to be significantly reduced when treated with Curc simultaneously. The study confirms that Met and Pio exert toxic effects on cardiac cells by generating oxidative stress. Curc, being an anti-oxidative molecule, can suppress this effect and, therefore, can be used as a supplement with anti-diabetic drugs to suppress the induced cardiac stress.

Keywords

Cardiotoxicity Metformin Pioglitazone Curcumin Oxidative stress Anti-diabetic Cardio-protective 

Notes

Acknowledgements

The present work was supported by a research funding granted to Dr. Vibha Rani by the Department of Biotechnology (DBT), Government of India (Ref No.: BT/PR3978/17/766/2011). We acknowledge Jaypee Institute of Information Technology, Deemed to be University and Department of Biotechnology, Govt. of India for providing the infrastructural support and funds, respectively. We would also like to acknowledge Dr. Papia Chowdury, Associate Professor, Department of Physics and Material Science, Jaypee Institute of Information Technology for assisting in spectrofluorometer related studies.

Compliance with ethical standards

Conflict of interest

There is no conflict of interest among the authors for the publication of this article.

References

  1. Agarwal AA, Jadhav PR, Deshmukh YA et al (2014) Prescribing pattern and efficacy of anti-diabetic drugs in maintaining optimal glycemic levels in diabetic patients. J Basic Clin Pharm 5(3):79–83CrossRefPubMedPubMedCentralGoogle Scholar
  2. Aggarwal BB, Sundaram C, Malani N et al (2006) Curcumin: the Indian solid gold. Adv Exp Med Biol 595:1–75Google Scholar
  3. American Diabetes Association (2009) Diagnosis and classification of diabetes mellitus. Diabetes Care 32(Suppl 1):S62–S67.  https://doi.org/10.2337/dc09-S062 CrossRefPubMedCentralGoogle Scholar
  4. An D, Kewalramani G, Chan JK et al (2006) Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3. Diabetologia 49(9):2174–2184CrossRefPubMedGoogle Scholar
  5. Anand P, Kunnumakkara AB, Newman RA et al (2007) Bioavailability of curcumin: problems and promises. Mol Pharm 4(6):807–818CrossRefPubMedGoogle Scholar
  6. Anfossi G, Russo I, Bonomo K et al (2011) The cardiovascular effects of metformin: further reasons to consider an old drug as a cornerstone in the therapy of type 2 diabetes mellitus. Curr Vasc Pharmacol 8(3):327–337CrossRefGoogle Scholar
  7. Asensio-Lopez MC, Lax A, Pascual-Figal DA et al (2011) Metformin protects against doxorubicin-induced cardiotoxicity: involvement of the adiponectin cardiac system. Free Radic Biol Med 51:1861–1871CrossRefPubMedGoogle Scholar
  8. Averill-Bates D, Grondin M, Ouellet F (2018) Activation of apoptosis signaling pathways by reactive oxygen species. Cryobiology 80:170CrossRefGoogle Scholar
  9. Bahtiyar G, Gutterman D, Lebovitz H (2016) Heart failure: a major cardiovascular complication of diabetes mellitus. Curr Diab Rep 16(11):116CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bugger H, Abel ED (2014) Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 57(4):660–671CrossRefPubMedPubMedCentralGoogle Scholar
  11. Carter WO, Narayanan PK, Robinson JP (1994) Intracellular hydrogen peroxide and superoxide anion detection in endothelial cells. J Leukoc Biol 55(2):253–258CrossRefPubMedGoogle Scholar
  12. Chen L, Magliano DJ, Zimmet PZ (2012) The worldwide epidemiology of type 2 diabetes mellitus—present and future perspectives. Nat Rev Endocrinol 8:228–236CrossRefGoogle Scholar
  13. Cummings BS, Schnellmann RG (2012) Measurement of cell death in mammalian cells. Curr Protoc Pharmacol 56(1):8–12CrossRefGoogle Scholar
  14. Deavall DG, Martin EA, Horner JM et al (2012) Drug-induced oxidative stress and toxicity. J Toxicol 2012:645460CrossRefPubMedPubMedCentralGoogle Scholar
  15. El Messaoudi S, Rongen GA, de Boer RA, Riksen NP (2011) The cardioprotective effects of metformin. Curr Opin Lipidol 22(6):445–453CrossRefPubMedGoogle Scholar
  16. Foretz M, Guigas B, Bertrand L et al (2014) Metformin: from mechanisms of action to therapies. Cell Metab 20(6):953–966CrossRefPubMedGoogle Scholar
  17. Fulda S, Gorman AM, Hori O et al (2010) Cellular stress responses: cell survival and Cell death. Int J Cell Biol 2010:1–23Google Scholar
  18. Gejl M, Starup-Linde J, Scheel-Thomsen J et al (2015) Risk of cardiovascular disease: the effects of diabetes and anti-diabetic drugs—a nested case–control study. Int J Cardiol 178:292–296CrossRefPubMedGoogle Scholar
  19. Halliwell B, Chirico S (1993) Lipid peroxidation: its mechanism, measurement, and significance. Am J Clin Nutr 57:715–725CrossRefGoogle Scholar
  20. Hosseinzadeh L, Behravan J, Mosaffa F et al (2011) Curcumin potentiates doxorubicin-induced apoptosis in H9c2 cardiac muscle cells through generation of reactive oxygen species. Food Chem Toxicol 49(5):1102–1109CrossRefPubMedGoogle Scholar
  21. Hostalek U, Gwilt M, Hildemann S (2015) Therapeutic use of metformin in pre diabetes and diabetes prevention. Drugs 75(10):1071–1094CrossRefPubMedPubMedCentralGoogle Scholar
  22. Huynh K, Bernardo BC, McMullen JR et al (2014) Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther 142(3):375–415CrossRefPubMedGoogle Scholar
  23. Iannello S, Milazzo P, Bordonaro F et al (2005) Effect of in vitro glucose and diabetic hyperglycemia on mouse kidney protein synthesis: relevance to diabetic microangiopathy. Med Gen Med 7(3):1Google Scholar
  24. Jain A, Rani V (2018) Mode of treatment governs curcumin response on doxorubicin-induced toxicity in cardiomyoblasts. Mol Cell Biochem 442(1–2):81–96CrossRefPubMedGoogle Scholar
  25. Kloppel G, Lohr M, Habich K et al (1985) Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Syn Pathol Res 4(2):110–125Google Scholar
  26. Kobayashi S, Xu X, Chen K et al (2012) Suppression of autophagy is protective in high glucose-induced cardiomyocyte injury. Autophagy 8(4):577–592CrossRefPubMedPubMedCentralGoogle Scholar
  27. Kohli S, Chhabra A, Jaiswal A et al (2013) Curcumin suppresses gelatinase B mediated norepinephrine induced stress in H9c2 cardiomyocytes. PLoS One 8:1–12CrossRefGoogle Scholar
  28. Kunwar A, Barik A, Priyadarsini KI et al (2007) Absorption and fluorescence studies of curcumin bound to liposome and living cells. BARC Newslett 285:213Google Scholar
  29. Leiber DC, Guengerich FP (2005) Elucidating mechanism of drug induced toxicity. Nat Rev Drug Discov 4:410–420CrossRefGoogle Scholar
  30. Lincon VJ, Walsh ML, Chen LB (1980) Localization of mitochondria in living cells with rhodamine 123. Proc Natl Acad Sci USA 77(2):990–994CrossRefGoogle Scholar
  31. Luo C-S, Liang J-R, Lin Q et al (2014) Cellular responses associated with ROS production and cell fate decision in early stress response to iron limitation in the diatom Thalassiosira pseudonana. J Proteome Res 13(12):5510–5523CrossRefPubMedPubMedCentralGoogle Scholar
  32. Mandavia CH, Aroor AR, DeMarco VG et al (2013) Molecular and metabolic mechanisms of cardiac dysfunction in diabetes. Life Sci 92(11):601–608CrossRefPubMedGoogle Scholar
  33. Messaoudi SE, Rongen GA, De Boer RA et al (2011) The cardioprotective effects of metformin. Curr Opin Lipidol 22(6):445–453CrossRefPubMedGoogle Scholar
  34. Mikhail N (2008) Combination therapy with DPP-4 inhibitors and pioglitazone in type 2 diabetes: theoretical consideration and therapeutic potential. Vasc Health Risk Manag 4(6):1221–1227CrossRefPubMedPubMedCentralGoogle Scholar
  35. Miki T, Yuda S, Kouzu H et al (2013) Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Fail Rev 18(2):149–166CrossRefPubMedGoogle Scholar
  36. Mittler R (2017) ROS are good. Trends Plant Sci 22(1):11–19CrossRefPubMedGoogle Scholar
  37. Mohan V, Bedi S, Unnikrishnan R, Sahay BK et al (2012) Pioglitazone—where do we stand in India? JAPI 60(1):68–70PubMedGoogle Scholar
  38. Nguyen HN, Ha PT, Sao Nguyen A et al (2016) Curcumin as fluorescent probe for directly monitoring in vitro uptake of curcumin combined paclitaxel loaded PLA-TPGS nanoparticles. Adv Nat Sci Nanosci Nanotechnol 7(2):025001CrossRefGoogle Scholar
  39. Nicholls DG (2012) Fluorescence measurement of mitochondrial membrane potential changes in cultured cells. Methods Mol Biol 10:119–133CrossRefGoogle Scholar
  40. Nowotny K, Jung T, Hohn A et al (2015) Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 5(1):194–222CrossRefPubMedPubMedCentralGoogle Scholar
  41. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358CrossRefPubMedGoogle Scholar
  42. Pai SA, Kshirsagar NA (2016) Pioglitazone utilization, efficacy and safety in Indian type 2 diabetic patients: a systematic review and comparison with European Medicines Agency Assessment Report. Indian J Med Res 144(5):672–681CrossRefPubMedPubMedCentralGoogle Scholar
  43. Patel SS, Goyal RK (2011) Cardioprotective effects of gallic acid in diabetes-induced myocardial dysfunction in rats. Pharmacogn Res 3(4):239–245CrossRefGoogle Scholar
  44. Pogatsa G (1996) What kind of cardiovascular alterations could be influenced positively by oral antidiabetic agents? Diabetes Res Clin Pract 31:S27–SS31CrossRefPubMedGoogle Scholar
  45. Prabst K, Engelhardt H, Ringgeler S et al (2017) Basic colorimetric proliferation assays: MTT, WST, and resazurin. Methods Mol Biol 1601:1–17CrossRefPubMedGoogle Scholar
  46. Rakovac I, Jeitler K, Gfrerer RJ et al (2005) Patients with type 2 diabetes treated with metformin: prevalence of contraindications and their correlation with discontinuation. Diabet Med 22(5):662–664CrossRefPubMedGoogle Scholar
  47. Rudy E (2007) Drugs that induce heart failure: an overview (part-1). Drug Ther Top ADR Focus 36(7):31–34Google Scholar
  48. Ryter SW, Kim HP, Hoetzel A et al (2007) Mechanisms of cell death in oxidative stress. Antioxid Redox Signal 9(1):49–89CrossRefPubMedGoogle Scholar
  49. Santulli G (2013) Epidemiology of cardiovascular disease in the 21st century: updated numbers and updated facts. The current epidemiology of CV disease. J Cardiovasc Dis Res 1(1):1Google Scholar
  50. Selvin E, Steffes MW, Zhu H et al (2010) Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med 362:800–811CrossRefPubMedPubMedCentralGoogle Scholar
  51. Shaw JE, Sicree RA, Zimmet PZ (2010) Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 87:4–14CrossRefPubMedGoogle Scholar
  52. Smith U (2001) Pioglitazone: mechanism of action. Int J Clin Pract Suppl 121:13–18Google Scholar
  53. Somparn P, Phisalaphong C, Nakornchai S et al (2007) Comparative antioxidant activities of curcumin and its demethoxy and hydrogenated derivatives. Biol Pharm Bull 30(1):74–78CrossRefPubMedGoogle Scholar
  54. Spiller HA, Quadrani DA (2004) Toxic effects from metformin exposure. Ann Pharmacother 38(5):776–780CrossRefPubMedGoogle Scholar
  55. Sterba M, Popelova O, Vavrova A et al (2013) Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxid Redox Signal 18(8):899–929CrossRefPubMedPubMedCentralGoogle Scholar
  56. Suzuki T (2010) Significance and limitation of changing the lifestyle among the elderly—strategies on the prevention of lifestyle-related diseases and long-term care state. Nihon Rinsho 68(5):953–968PubMedGoogle Scholar
  57. Tanne JH (2007) FDA places “black box” warning on anti diabetes drugs. BMJ 334(7606):1237PubMedPubMedCentralGoogle Scholar
  58. Umadevi S, Gopi V, Simna SP et al (2012) Studies on the cardio protective role of gallic acid against AGE-induced cell proliferation and oxidative stress in H9c2 (2-1) cells. Cardiovasc Toxicol 12:304–311CrossRefPubMedGoogle Scholar
  59. Varga ZV, Ferdinandy P, Liaudet L (2015) Drug-induced mitochondrial dysfunction and cardiotoxicity. Am J Physiol Heart Circ Physiol 309(9):H1453–H1467CrossRefPubMedPubMedCentralGoogle Scholar
  60. Watkins S, Borthwick G, Arthur H (2011) The H9C2 cell line and primary neonatal cardiomyocyte cells show similar hypertrophic responses in vitro. In Vitro Cell Dev Biol Anim 47:125–131CrossRefPubMedGoogle Scholar
  61. Wongcharoen W, Phrommintikul A (2009) The protective role of curcumin in cardiovascular diseases. Int J Cardiol 133(2):145–151CrossRefPubMedGoogle Scholar
  62. Yagi S, Drouart N, Bourgaud F et al (2012) Antioxidant and antiglycation properties of Hydnora johannis roots. S Afr J Bot 84:124–127CrossRefGoogle Scholar
  63. Zhou G, Myers R, Li Y et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Investig 108(8):1167–1174CrossRefPubMedGoogle Scholar
  64. Zordoky BN, El-Kadi AO (2007) H9C2 cell line is a valuable in vitro model to study the drug metabolizing enzymes in the heart. J Pharmacol Toxicol Methods 56:317–322CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Transcriptome Laboratory, Centre for Emerging Diseases, Department of BiotechnologyJaypee Institute of Information TechnologyNoidaIndia

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