The Potent Cytotoxic and Oxidative Effects of β-2 Selective ICI-118,551 on Breast Adenocarcinoma Cell Lines with Different Aggressiveness

Objective: Beta-blockers are a group of drugs used in the treatment of cardiovascular ailments. On the other hand, the potential anticancer effects of these drugs have become increasingly important in recent two decades. In this paper, the effects of beta-1 selective esmolol, beta-2 selective ICI-118,551 and non-selective nadolol on breast cancer cell lines with different aggressiveness were investigated for the first time. Methods: A standard spectrophotometric MTT assay was used to determine cell viability. Catalase activities and malondialdehyde levels were measured spectrophotometrically based on the reduction of absorbance resulted from hydrogen peroxide decomposition and the formation of thiobarbituric acid- malondialdehyde product, respectively. Results: It was found that beta-2 selective ICI-118,551 was the most effective one among investigated blockers against MCF-7 and MDA-MB-231 cell lines. Additionally, it was seen that 50-150 µM ICI-118,551 treatment for 48 hours significantly changed catalase activities and malondialdehyde levels of both breast cancer cell lines in favour of radical production. Conclusion: The obtained results showed that beta-2 adrenergic receptor specific antagonism plays a significant role in beta-blocker induced breast cancer cell death. The outstanding suppression in catalase activities and concomitant increases in radical levels appear to contribute to potent cytotoxic effect of ICI-118,551 on breast adenocarcinoma. Consequently, it can be clearly interpreted that ICI-118,551 may be a valuable option in the treatment of breast cancer.

Keywords:

Esmolol, ICI-118, 551, Nadolol Breast Adenocarcinoma,

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1. Frishman WH, Saunders E. β-Adrenergic blockers. J Clin Hypertens 2011; 13(9): 649-653.
2. Haas MJ, Kurban W, Shah H, Onstead-Haas L, Mooradian AD. Beta blockers suppress dextrose-induced endoplasmic reticulum stress, oxidative stress, and apoptosis in human coronary artery endothelial cells. Am J Ther 2016; 23: 1524-1531.
3. Brehm BR, Wolf SC, Bertsch D, Klaussner M, Wesselborg S, Schüler S, Schulze-Osthoff K. Effects of nebivolol on proliferation and apoptosis of human coronary artery smooth muscle and endothelial cells. Cardiovasc Res 2001; 49: 430-439.
4. Uzar E, Acar A, Evliyaoğlu O, Fırat U, Kamasak K, Göçmez C, Alp H, Tüfek A, Taşdemir N, İlhan A. The anti-oxidant and anti-apoptotic effects of nebivolol and zofenopril in a model of cerebral ischemia/reperfusion in rats. Prog Neuro-Psychoph 2012; 36: 22-28.
5. Serpi R, Tolonen AM, Tenhunen O, Pieviläinen O, Kubin AM, Vaskivuo T, Soini Y, Kerkelä R, Leskinen H, Ruskoaho H. Divergent effects of losartan and metoprolol on cardiac remodeling, C‐kit+ cells, proliferation and apoptosis in the left ventricle after myocardial infarction. Clin Transl Sci 2009; 2: 422-430.
6. Su Q, Li L, Liu YC, Zhou Y, Lu YG, Wen WM. Effect of metoprolol on myocardial apoptosis and caspase-9 activation after coronary microembolization in rats. Exp Clin Cardiol 2013; 18(2): 161.
7. Li W, Yan S, Zhao J, Ding X, Zhang S, Wang D, LiuL, Peng W, Li H, Wang D, Liu Z, Liu Y. Metoprolol inhibits cardiac apoptosis and fibrosis in a canine model of chronic obstructive sleep apnea. Cell Physiol Biochem 2015; 36(3): 1131-1141.
8. Smith SKS, Smith DM. Beta blockade induces apoptosis in cultured capillary endothelial cells. In Vitro Cell Dev-An 2002; 38: 298-304.
9. Diaz ES, Karlan BY, Li AJ. Impact of beta blockers on epithelial ovarian cancer survival. Gynecol Oncol 2012; 127: 375-378.
10. Powe DG, Voss MJ, Zänker KS, Habashy HO, Green AR, Ellis IO, Entschladen F. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget 2010; 1: 628.
11. Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K. Beta blockers and breast cancer mortality: a population-based study. J Clin Oncol 2011; 29: 2635-2644.
12. Ji Y, Li K, Xiao X, Zheng S, Xu T, Chen S. Effects of propranolol on the proliferation and apoptosis of hemangioma-derived endothelial cells. J Pediatr Surg 2012; 47: 2216-2223.
13. Wong A, Hardy KL, Kitajewski AM, Shawber CJ, Kitajewski JK, Wu JK. Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells. Plast Reconstr Surg 2012; 130: 1012.
14. Tu JB, Ma RZ, Dong Q, Jiang F, Hu XY, Li QY., Pattar P, Zhang H. Induction of apoptosis in infantile hemangioma endothelial cells by propranolol. Exp Ther Med 2013; 6: 574-578.
15. Ma X, Zhao T, Ouyang T, Xin S, Ma Y, Chang M. Propranolol enhanced adipogenesis instead of induction of apoptosis of hemangiomas stem cells. Int J Clin Exp Patho 2014; 7: 3809.
16. Albiñana V, de las Heras KVG, Serrano-Heras G, Segura T, Perona-Moratalla AB, Mota-Pérez M, de Campos JM, Botella LM. Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patients. Orphanet J Rare Dis 2015; 10: 118.
17. Wnęk A, Andrzejewska E, Kobos J, Taran K, Przewratil P. Molecular and immunohistochemical expression of apoptotic proteins Bax, Bcl-2 and Caspase 3 in infantile hemangioma tissues as an effect of propranolol treatment. Immunol Lett 2017; 185: 27-31.
18. Zhang D, Ma Q, Shen S, Hu H. Inhibition of pancreatic cancer cell proliferation by propranolol occurs through apoptosis induction: the study of β-adrenoceptor antagonist's anticancer effect in pancreatic cancer cell. Pancreas 2009; 38: 94-100.
19. Liao X, Che X, Zhao W, Zhang D, Bi T, Wang G. The β-adrenoceptor antagonist, propranolol, induces human gastric cancer cell apoptosis and cell cycle arrest via inhibiting nuclear factor κB signaling. Oncol Rep 2010; 24: 1669-1676.
20. Wolter JK, Wolter NE, Blanch A, Partridge T, Cheng L, Morgenstern DA, Podkowa M, Kaplan DR, Irwin MS. Anti-tumor activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma. Oncotarget 2014; 5: 161.
21. Zhou C, Chen X, Zeng W, Peng C, Huang G, Li XA, Zhengxiao O, Luo Y, Xu X, Xu B, Wang W, He R, Zhang X, Zhang L, Liu J, Knepper TC, He Y, McLeod HL. Propranolol induced G0/G1/S phase arrest and apoptosis in melanoma cells via AKT/MAPK pathway. Oncotarget 2016; 7: 68314.
22. Green LM, Reade JL, Ware CF. Rapid colorimetric assay for cell viability: application to the quantitation of cytotoxic and growth inhibitory lymphokines. J Immunol Methods 1984; 70: 257-268.
23. Aebi H. Catalase. Bergmeyer HU, editor. Methods of enzymatic analysis. Academic Press; 1974.p.673-684.
24. Schmedes A, Hølmer G. A new thiobarbituric acid (TBA) method for determining free malondialdehyde (MDA) and hydroperoxides selectively as a measure of lipid peroxidation. J Am Oil Chem Soc 1989; 66(6): 813-817.
25. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72(1-2): 248-254.
26. Gründker C, Föst C, Fister S, Nolte N, Günthert AR, Emons G. Gonadotropin-releasing hormone type II antagonist induces apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells in vitro and in vivo. Breast Cancer Res 2010; 12(4): 1-9.
27. Xie WY, He RH, Zhang J, He YJ, Wan Z, Zhou CF, Tang YJ, Li Z, Mcleod HL, Liu J. β‑blockers inhibit the viability of breast cancer cells by regulating the ERK/COX‑2 signaling pathway and the drug response is affected by ADRB2 single‑nucleotide polymorphisms. Oncol Rep 2019; 41(1): 341-350.
28. Chin CC, Li JM, Lee KF, Huang YC, Wang KC, Lai HC, Cheng CC, Kuo YH, Shi CS. Selective β2‐AR blockage suppresses colorectal cancer growth through regulation of EGFR‐Akt/ERK1/2 signaling, G1‐phase arrest, and apoptosis. J Cellular Physiol 2016; 231(2): 459-472.
29. Liu X, Wu WK, Yu L, Sung JJ, Srivastava G, Zhang ST, Cho CH. Epinephrine stimulates esophageal squamous‐cell carcinoma cell proliferation via β‐adrenoceptor‐dependent transactivation of extracellular signal‐regulated kinase/cyclooxygenase‐2 pathway. J Cell Biochem 2008; 105(1): 53-60.
30. Magsino Jr CH, Hamouda W, Bapna V, Ghanim H, Abu-Reish IA, Aljada A, Dandona P. Nadolol inhibits reactive oxygen species generation by leukocytes and linoleic acid oxidation. Am J Cardiol 2000; 86: 443-448.
31. Sharma B, Daga MK, Gambhir DS, Kaushik M. Effect of esmolol, an ultra-short acting beta blocker on oxidant status and antioxidant activity in acute myocardial infarction: Results of a randomized double-blind, controlled, prospective clinical study. Chest 2003; 124: 152S.