Sensitivity of Human Leukemic Cells to Carvedilol

Document Type : Research Paper

Authors

Department of Immunology, Faculty of Medicine, Shahed University, Tehran, Iran

Abstract

Background and Objective: Carvedilol, a non-specific β-blocker, has been used for treatment of hypertension, stroke and congestive heart failure. The therapeutic effects of β blockers in cancer patients have been shown. Carvedilol has considerable anti-inflammatory, anti-tumor and anti-angiogenic properties. In this study, the effects of carvedilol on proliferation of human U937 and Molt-4 leukemic cells were studied in vitro.
Materials and Methods: Human leukemic T cells [Molt-4] and monocytes [U937] were cultured in Roswell Park Memorial Institute (RPMI) 1640 complete medium and were treated with different concentrations of carvedilol (1, 5, 10, 20, 50 and 100 μg/ml) for 24, 48 and 72 hours. The cytotoxicity of carvedilol on U937 and Molt-4 cells was determined using MTT (3-[4, 5 dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide) assay.
Results: Carvedilol significantly decreased human U937 and Molt-4 leukemic cells proliferation, concentration- and time-dependently in comparison with control cells.
Conclusion: According to our results, carvedilol has anti-proliferative effect on U937 and Molt-4 leukemic cells in a concentration- and time-dependent manner. Thus, carvedilol might be a useful candidate for treatment of leukemic patients as well as other cancers.

Keywords


  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a Cancer Journal for Clinicians 2018;68(6):394-424.
  2. Abubakar II, Tillmann T, Banerjee A. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;385(9963):117-71.
  3. Pirani N, Khiavi FF. Population Attributable Fraction for Cardiovascular Diseases Risk Factors in Selected Countries: A comparative study. Materia Socio-Medica 2017;29(1):35-9.
  4. Keating GM, Jarvis B. Carvedilol: a review of its use in chronic heart failure. Drugs 2003;63(16):1697-741.
  5. Koohi F, Salehiniya H, Shamlou R, Eslami S, Ghojogh ZM, Kor Y, et al. Leukemia in Iran: Epidemiology and Morphology Trends. Asian Pac Journal of Cancer Prevention 2015;16(17):7759-63.
  6. Malvezzi M, Carioli G, Bertuccio P, Rosso T, Boffetta P, Levi F, La Vecchia C, Negri E. European cancer mortality predictions for the year 2016 with focus on leukaemias. Annals of Oncology 2016;27(4):725-31.
  7. Greaves M. Leukaemia 'firsts' in cancer research and treatment. Nature Reviews Cancer 2016;16(3):163-72.
  8. Greaves M. Leukaemia'firsts' in cancer research and treatment. Nature Reviews Cancer 2016;16(3):163.
  9. Reiter MJ. Cardiovascular drug class specificity: β-blockers. Progress in Cardiovascular Diseases 2004;47(1):11-33.
  10. Stanojkovic TP, Zizak Z, Mihailovic-Stanojevic N, Petrovic T, Juranic Z. Inhibition of proliferation on some neoplastic cell lines-act of carvedilol and captopril. Journal of Experimental and Clinical Cancer Research 2005;24(3):387-95.
  11. Chen Y, Hong X. Effects of carvedilol reduce conjunctivitis through changes in inflammation, NGF and VEGF levels in a rat model. Experimental and Therapeutic Medicine 2016;11(5):1987-92.
  12. Wang D, Chen Y, Jiang J, Zhou A, Pan L, Chen Q, et al. Carvedilol has stronger anti-inflammation and anti-virus effects than metoprolol in murine model with coxsackievirus B3-induced viral myocarditis. Gene 2014;547(2):195-201.
  13. Amirshahrokhi K, Khalili AR. Carvedilol attenuates paraquat-induced lung injury by inhibition of proinflammatory cytokines, chemokine MCP-1, NF-kappaB activation and oxidative stress mediators. Cytokine 2016;88:144-53.
  14. Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K. Beta blockers and breast cancer mortality: a population- based study. Journal of Clinical Oncology 2011;29(19):2635-44.
  15. Diaz ES, Karlan BY, Li AJ. Impact of beta blockers on epithelial ovarian cancer survival. Journal of Clinical Oncology 2012;127(2):375-8.
  16. Wang HM, Liao ZX, Komaki R, Welsh JW, O'Reilly MS, Chang JY, et al. Improved survival outcomes with the incidental use of beta-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy. Annals of Oncology 2013;24(5):1312-9.
  17. Al-Wadei HA, Al-Wadei MH, Schuller HM. Prevention of pancreatic cancer by the beta-blocker propranolol. Anti-cancer drugs 2009;20(6):477-82.
  18. Choi CH, Song T, Kim TH, Choi JK, Park JY, Yoon A, et al. Meta-analysis of the effects of beta blocker on survival time in cancer patients. Journal of Cancer Research and Clinical Oncology 2014;140(7):1179-88.
  19. Lin CS, Lin WS, Lin CL, Kao CH. Carvedilol use is associated with reduced cancer risk: A nationwide population-based cohort study. International Journal of Cardiology 2015;184:9-13.
  20. Chang A, Yeung S, Thakkar A, Huang KM, Liu MM, Kanassatega RS, et al. Prevention of skin carcinogenesis by the beta-blocker carvedilol. Cancer Prevention Research 2015;8(1):27-36.
  21. Dezong G, Zhongbing M, Qinye F, Zhigang Y. Carvedilol suppresses migration and invasion of malignant breast cells by inactivating Src involving cAMP/PKA and PKCdelta signaling pathway. Journal of Cancer Research and Therapeutics 2014;10(4):998-1003.
  22. Pasquier E, Street J, Pouchy C, Carre M, Gifford AJ, Murray J, et al. beta-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma. British Journal of Cancer 2013;108(12):2485-94.
  23. Balaha M, Kandeel S, Barakat W. Carvedilol suppresses circulating and hepatic IL-6 responsible for hepatocarcinogenesis of chronically damaged liver in rats. Toxicology and Applied Pharmacology 2016;311:1-11.
  24. Hajighasemi F, Mirshafiey A. In vitro sensitivity of leukemia cells to propranolol. Journal of Clinical Medicine Research 2009;1(3):144-9.
  25. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of Immunological Methods 1983;65(1-2):55-63.
  26. Cheng JS, Huang CC, Chou CT, Jan CR. Mechanisms of carvedilol-induced [Ca2+] i rises and death in human hepatoma cells. Naunyn-Schmiedeberg's Archives of Pharmacology 2007;376(3):185-94.
  27. Cheng SM, Yang SP, Ho LJ, Tsao TP, Chang DM, Lai JH. Carvedilol modulates in-vitro granulocyte-macrophage colony-stimulating factor-induced interleukin-10 production in U937 cells and human monocytes. Immunological Investigations 2003;32(1-2):43-58.
  28. Iseri OD, Sahin FI, Terzi YK, Yurtcu E, Erdem SR, Sarialioglu F. beta-Adrenoreceptor antagonists reduce cancer cell proliferation, invasion, and migration. Pharmaceutical Biology 2014;52(11):1374-81.
  29. Coelho M, Moz M, Correia G, Teixeira A, Medeiros R, Ribeiro L. Antiproliferative effects of beta-blockers on human colorectal cancer cells. Oncology Reports 2015;33(5):2513-20.
  30. Wrobel LJ, Le Gal FA. Inhibition of human melanoma growth by a non-cardioselective beta-blocker. The Journal of Investigative Dermatology 2015;135(2):525-31.
  31. Yap A, Lopez-Olivo MA, Dubowitz J, Pratt G, Hiller J, Gottumukkala V, et al. Effect of beta-blockers on cancer recurrence and survival: a meta-analysis of epidemiological and perioperative studies. British Journal of Anaesthesia 2018;121(1):45-57.
  32. Watkins JL, Thaker PH, Nick AM, Ramondetta LM, Kumar S, Urbauer DL, et al. Clinical impact of selective and nonselective beta-blockers on survival in patients with ovarian cancer. Cancer 2015;121(19):3444-51.
  33. Raimondi S, Botteri E, Munzone E, Cipolla C, Rotmensz N, DeCensi A, et al. Use of beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and breast cancer survival: Systematic review and meta-analysis. The International Journal of Cancer 2016;139(1):212-9.
  34. Lu H, Liu X, Guo F, Tan S, Wang G, Liu H, et al. Impact of beta-blockers on prostate cancer mortality: a meta-analysis of 16,825 patients. Onco Targets and Therapy 2015;8:985-90.
  35. Jansen L, Hoffmeister M, Arndt V, Chang-Claude J, Brenner H. Stage-specific associations between beta blocker use and prognosis after colorectal cancer. Cancer 2014;120(8):1178-86.
  36. Nagaraja AS, Sadaoui NC, Lutgendorf SK, Ramondetta LM, Sood AK. beta-blockers: a new role in cancer chemotherapy? Expert Opinion on Investigational Drugs 2013;22(11):1359-63.
  37. Coelho M, Soares-Silva C, Brandao D, Marino F, Cosentino M, Ribeiro L. beta-Adrenergic modulation of cancer cell proliferation: available evidence and clinical perspectives. Journal of Cancer Research and Clinical Oncology 2017;143(2):275-91.
  38. Cole SW, Sood AK. Molecular pathways: beta-adrenergic signaling in cancer. Clinical cancer research : an Official Journal of the American Association for Cancer Research 2012;18(5):1201-6.