Vol 14, No 5 (2018)
Review paper
Published online: 2019-02-15

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Anti-cancer agents and endothelium

Renata Pacholczak12, Jerzy Dropiński3, Jerzy Walocha1, Jacek Musiał3
Oncol Clin Pract 2018;14(5):249-256.

Abstract

Recent advances in oncology have improved the treatment outcomes and life expectancy of cancer patients; therefore, late effects of oncological treatment are of high clinical importance. Recent studies have shown that cardiovascular events are among the leading causes of premature morbidity in cancer survivors. Cardiotoxicity of some chemotherapeutic agents have been already confirmed; however, this issue seems to be more complex. Endothelium dysfunction is one of the first recognisable signs of atherosclerosis, which occurs long before the development of overt cardiovascular disease. Thus, it could be considered as an initial step, leading to increased risk of cardiovascular events. This process is not easy to recognise; however, there are some laboratory tests and imagining techniques that provide an insight into the progression of endothelial dysfunction. In this review we discuss the influence of oncological treatment on endothelium, according to the hypothesis that it increases cardiovascular morbidity and mortality in cancer survivors. Additionally, we present diagnostic and therapeutic measures that could reduce cardiovascular risk in cancer patients.

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References

  1. Mulrooney DA, Blaes AH, Duprez D. Vascular injury in cancer survivors. J Cardiovasc Transl Res. 2012; 5(3): 287–295.
  2. Hooning MJ, Botma A, Aleman BMP, et al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst. 2007; 99(5): 365–375.
  3. Jang WJ, Choi DY, Jeon IS. Vascular endothelial dysfunction after anthracyclines treatment in children with acute lymphoblastic leukemia. Korean J Pediatr. 2013; 56(3): 130–134.
  4. Jenei Z, Bárdi E, Magyar MT, et al. Anthracycline causes impaired vascular endothelial function and aortic stiffness in long term survivors of childhood cancer. Pathol Oncol Res. 2013; 19(3): 375–383.
  5. Reilley MJ, Jacobs LA, Vaughn DJ, et al. Cardiovascular risk in long-term survivors of testicular cancer. Cancer. 2008; 112(9): 1949–1953.
  6. Schimmel KJM, Richel DJ, van den Brink RBA, et al. Cardiotoxicity of cytotoxic drugs. Cancer Treat Rev. 2004; 30(2): 181–191.
  7. Yeh ETH, Tong AT, Lenihan DJ, et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation. 2004; 109(25): 3122–3131.
  8. Khouri MG, Douglas PS, Mackey JR, et al. Cancer therapy-induced cardiac toxicity in early breast cancer: addressing the unresolved issues. Circulation. 2012; 126(23): 2749–2763.
  9. Haykowsky MJ, Mackey JR, Thompson RB, et al. Cardiovascular risk profile of patients with HER2/neu-positive breast cancer treated with anthracycline-taxane-containing adjuvant chemotherapy and/or trastuzumab. Cancer Epidemiol Biomarkers Prev. 2007; 16(5): 1026–1031.
  10. Brunner H, Cockcroft JR, Deanfield J, et al. Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens. 2005; 23(2): 233–246.
  11. Widlansky ME, Gokce N, Keaney JF, et al. The clinical implications of endothelial dysfunction. J Am Coll Cardiol. 2003; 42(7): 1149–1160.
  12. Govers R, Rabelink TJ. Cellular regulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol. 2001; 280(2): F193–F206.
  13. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007; 115(10): 1285–1295.
  14. Graham I, Atar D, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary: Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (Constituted by representatives of nine societies and by invited experts). European Heart Journal. 2007; 28(19): 2375–2414.
  15. Liao JK. Linking endothelial dysfunction with endothelial cell activation. J Clin Invest. 2013; 123(2): 540–541.
  16. Erdbruegger U, Haubitz M, Woywodt A. Circulating endothelial cells: a novel marker of endothelial damage. Clin Chim Acta. 2006; 373(1-2): 17–26.
  17. Meroni PL, Borghi MO, Raschi E, et al. Inflammatory response and the endothelium. Thromb Res. 2004; 114(5-6): 329–334.
  18. Verma S, Buchanan MR, Anderson TJ. Endothelial function testing as a biomarker of vascular disease. Circulation. 2003; 108(17): 2054–2059.
  19. Landim MB, Casella Filho A, Chagas AC. Asymmetric dimethylarginine (ADMA) and endothelial dysfunction: implications for atherogenesis. Clinics (Sao Paulo). 2009; 64(5): 471–478.
  20. Böger RH, Vallance P, Cooke JP. Asymmetric dimethylarginine (ADMA): a key regulator of nitric oxide synthase. Atheroscler Suppl. 2003; 4(4): 1–3.
  21. Healy B, Ojrio C. Endothelial Cell Dysfunction : An Emerging Endocrinopathy Linked To Coronary Disease. JACC. 1990; 16(2): 7–8.
  22. Harris RA, Nishiyama SK, Wray DW, et al. Ultrasound assessment of flow-mediated dilation. Hypertension. 2010; 55(5): 1075–1085.
  23. Morganti M, Carpi A, Nicolini A, et al. Atherosclerosis and cancer: common pathways on the vascular endothelium. Biomed Pharmacother. 2002; 56(7): 317–324.
  24. Kebers F, Lewalle JM, Desreux J, et al. Induction of endothelial cell apoptosis by solid tumor cells. Exp Cell Res. 1998; 240(2): 197–205.
  25. de Vos FY, Willemse PHB, de Vries EGE, et al. Endothelial cell effects of cytotoxics: balance between desired and unwanted effects. Cancer Treat Rev. 2004; 30(6): 495–513.
  26. Minotti G, Menna P, Salvatorelli E, et al. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004; 56(2): 185–229.
  27. Duquaine D, Hirsch GA, Chakrabarti A, et al. Rapid-onset endothelial dysfunction with adriamycin: evidence for a dysfunctional nitric oxide synthase. Vasc Med. 2003; 8(2): 101–107.
  28. Vásquez-Vivar J, Martasek P, Hogg N, et al. Endothelial nitric oxide synthase-dependent superoxide generation from adriamycin. Biochemistry. 1997; 36(38): 11293–11297.
  29. Rajagopalan S, Politi PM, Sinha BK, et al. Adriamycin-induced free radical formation in the perfused rat heart: implications for cardiotoxicity. Cancer Res. 1988; 48(17): 4766–4769.
  30. Volkova M, Russell R. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev. 2011; 7(4): 214–220.
  31. Murata T, Yamawaki H, Yoshimoto R, et al. Chronic effect of doxorubicin on vascular endothelium assessed by organ culture study. Life Sci. 2001; 69(22): 2685–2695.
  32. Wu S, Ko YS, Teng MS, et al. Adriamycin-induced cardiomyocyte and endothelial cell apoptosis: in vitro and in vivo studies. J Mol Cell Cardiol. 2002; 34(12): 1595–1607.
  33. Majzner K, Wojcik T, Szafraniec E, et al. Nuclear accumulation of anthracyclines in the endothelium studied by bimodal imaging: fluorescence and Raman microscopy. Analyst. 2015; 140(7): 2302–2310.
  34. Lundman P, Eriksson MJ, Stühlinger M, et al. Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine. J Am Coll Cardiol. 2001; 38(1): 111–116.
  35. Chow AY, Chin C, Dahl G, et al. Anthracyclines cause endothelial injury in pediatric cancer patients: a pilot study. J Clin Oncol. 2006; 24(6): 925–928.
  36. Ryberg M. Cardiovascular toxicities of biological therapies. Semin Oncol. 2013; 40(2): 168–177.
  37. Hotchkiss KA, Ashton AW, Mahmood R, et al. Inhibition of Endothelial Cell Function in Vitro and Angiogenesis in Vivo by Docetaxel ( Taxotere ): Association with Impaired Repositioning of the Microtubule Organizing Center 1 Supported by grants from the National Cancer P01-CA13330 ), Aventis Pharmac. 2002;1(November):1191-1200.
  38. Morbidelli L, Donnini S, Ziche M. Targeting endothelial cell metabolism for cardio-protection from the toxicity of antitumor agents. Cardio-Oncology. 2016; 2(1).
  39. Milross CG, Mason KA, Hunter NR, et al. Enhancement of tumor radioresponse of a murine mammary carcinoma by paclitaxel. Cancer Res. 1994; 54(13): 3506–3510.
  40. Verweij J, Clavel M, Chevalier B. Paclitaxel (Taxol) and docetaxel (Taxotere): not simply two of a kind. Ann Oncol. 1994; 5(6): 495–505.
  41. Salvatorelli E, Menna P, Cascegna S, et al. Paclitaxel and docetaxel stimulation of doxorubicinol formation in the human heart: implications for cardiotoxicity of doxorubicin-taxane chemotherapies. J Pharmacol Exp Ther. 2006; 318(1): 424–433.
  42. Vassilakopoulou M, Mountzios G, Papamechael C, et al. Paclitaxel chemotherapy and vascular toxicity as assessed by flow-mediated and nitrate-mediated vasodilatation. Vascul Pharmacol. 2010; 53(3-4): 115–121.
  43. Belotti D, Vergani V, Drudis T, et al. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res. 1996; 2(11): 1843–1849.
  44. Gamble GE, Tyrrell P. Acute stroke following cisplatin therapy. Clinical Oncology. 1998; 10(4): 274–275.
  45. Içli F, Karaoğuz H, Dinçol D, et al. Severe vascular toxicity associated with cisplatin-based chemotherapy. Cancer. 1993; 72(2): 587–593.
  46. Czaykowski PM, Moore MJ, Tannock IF. High risk of vascular events in patients with urothelial transitional cell carcinoma treated with cisplatin based chemotherapy. J Urol. 1998; 160(6 Pt 1): 2021–2024.
  47. Shi Y, Inoue S, Shinozaki R, et al. Release of cytokines from human umbilical vein endothelial cells treated with platinum compounds in vitro. Jpn J Cancer Res. 1998; 89(7): 757–767.
  48. Gietema JA, Meinardi MT, Messerschmidt J, et al. Circulating plasma platinum more than 10 years after cisplatin treatment for testicular cancer. Lancet. 2000; 355(9209): 1075–1076.
  49. Meinardi MT, Gietema DJ, van Veldhuisen† W. Long-term chemotherapy-related cardiovascular morbidity. Cancer Treat Rev. 2000; 26(1): 269–286.
  50. Nuver J, De Haas EC, Van Zweeden M, et al. Vascular damage in testicular cancer patients: a study on endothelial activation by bleomycin and cisplatin in vitro. Oncol Rep. 2010; 23(1): 247–253.
  51. Dieckmann KP, Struss WJ, Budde U. Evidence for acute vascular toxicity of cisplatin-based chemotherapy in patients with germ cell tumour. Anticancer Res. 2011; 31(12): 4501–4505.
  52. Nuver J, Smit AJ, van der Meer J, et al. Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer. J Clin Oncol. 2005; 23(36): 9130–9137.
  53. Togna GI, Togna AR, Franconi M, et al. Cisplatin triggers platelet activation. Thromb Res. 2000; 99(5): 503–509.
  54. Bonita R, Pradhan R. Cardiovascular toxicities of cancer chemotherapy. Semin Oncol. 2013; 40(2): 156–167.
  55. Taniguchi I. Clinical Significance of Cyclophosphamide-induced Cardiotoxicity. Intern Med. 2005; 44(2): 89–90.
  56. Colleoni M, Rocca A, Sandri MT, et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002; 13(1): 73–80.
  57. Folkman J. New perspectives in clinical oncology from angiogenesis research. Eur J Cancer. 1996; 32A(14): 2534–2539.
  58. Kachel DL, Martin WJ. Cyclophosphamide-induced lung toxicity: mechanism of endothelial cell injury. J Pharmacol Exp Ther. 1994; 268(1): 42–46.
  59. Bocci G, Nicolaou K, Kerbel R. Protracted Low-Dose Effects on Human Endothelial Cell Proliferation and Survival in Vitro Reveal a Selective Antiangiogenic Window for Various Chemotherapeutic Drugs. Cancer Res. 2002:6938-6943. http://cancerres.aacrjournals.org/cgi/content/abstract/62/23/6938%5Cnpapers2://publication/uuid/024740E1-87EE-43D7-AC32-90260C1B9C25.
  60. Cwikiel M, Eskilsson J, Wieslander JB, et al. The appearance of endothelium in small arteries after treatment with 5-fluorouracil. An electron microscopic study of late effects in rabbits. Scanning Microsc. 1996; 10(3): 805–18; discussion 819.
  61. Cwikiel M, Zhang B, Eskilsson J, et al. The influence of 5-fluorouracil on the endothelium in small arteries. An electron microscopic study in rabbits. Scanning Microsc. 1995; 9(2): 561–576.
  62. Cwikiel M, Eskilsson J, Albertsson M, et al. The influence of 5-fluorouracil and methotrexate on vascular endothelium. An experimental study using endothelial cells in the culture. Ann Oncol. 1996; 7(7): 731–737.
  63. Focaccetti C, Bruno A, Magnani E, et al. Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes. PLoS One. 2015; 10(2): e0115686.
  64. Kuzel T, Esparaz B, Green D, et al. Thrombogenicity of intravenous 5-fluorouracil alone or in combination with cisplatin. Cancer. 1990; 65(4): 885–889, doi: 10.1002/1097-0142(19900215)65:4<885::aid-cncr2820650410>3.0.co;2-h.
  65. Kim SM, Kwak CH, Lee B, et al. A case of severe coronary spasm associated with 5-fluorouracil chemotherapy. Korean J Intern Med. 2012; 27(3): 342–345.
  66. Mosseri M, Fingert HJ, Varticovski L, et al. In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle. Cancer Res. 1993; 53(13): 3028–3033.
  67. Südhoff T, Enderle MD, Pahlke M, et al. 5-Fluorouracil induces arterial vasocontractions. Ann Oncol. 2004; 15(4): 661–664.
  68. Berardi R, Caramanti M, Savini A, et al. State of the art for cardiotoxicity due to chemotherapy and to targeted therapies: a literature review. Crit Rev Oncol Hematol. 2013; 88(1): 75–86.
  69. Choueiri TK, Mayer EL, Je Y, et al. Congestive heart failure risk in patients with breast cancer treated with bevacizumab. J Clin Oncol. 2011; 29(6): 632–638.
  70. Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007; 96(12): 1788–1795.
  71. Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock. New England Journal of Medicine. 2012; 367(14): 1287–1296.
  72. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007; 99(16): 1232–1239.
  73. Veronese ML, Mosenkis A, Flaherty KT, et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol. 2006; 24(9): 1363–1369.
  74. Mir O, Mouthon L, Alexandre J, et al. Bevacizumab-induced cardiovascular events: a consequence of cholesterol emboli syndrome? J Natl Cancer Inst. 2007; 99(1): 85–86.
  75. Thijs AMJ, van Herpen CML, Sweep FC, et al. Role of endogenous vascular endothelial growth factor in endothelium-dependent vasodilation in humans. Hypertension. 2013; 61(5): 1060–1065.
  76. Mourad JJ, des Guetz G, Debbabi H, et al. Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol. 2008; 19(5): 927–934.
  77. Thijs AMJ, van Herpen CML, Verweij V, et al. Impaired endothelium-dependent vasodilation does not initiate the development of sunitinib-associated hypertension. J Hypertens. 2015; 33(10): 2075–2082.
  78. Chintalgattu V, Rees ML, Culver JC, et al. Coronary microvascular pericytes are the cellular target of sunitinib malate-induced cardiotoxicity. Sci Transl Med. 2013; 5(187): 187ra69.
  79. Lindahl P, Betsholtz C, Lindahl P, et al. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science. 1997; 277(5323): 242–245.
  80. Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007; 7(5): 332–344.
  81. Ushio-fukai M, Griendling KK, Becker PL, et al. Ionizing Radiation Accelerates Aortic Lesion Formation in Fat-Fed Mice via SOD-Inhibitable Processes. Arter Thromb Vasc Biol. 2014(February): 1387–1393.
  82. Dunsmore LD, LoPonte MA, Dunsmore RA. Radiation-induced coronary artery disease. J Am Coll Cardiol. 1986; 8(1): 239–244.
  83. Hashmonai M, Elami A, Kuten A, et al. Subclavian artery occlusion after radiotherapy for carcinoma of the breast. Cancer. 1988; 61(10): 2015–2018, doi: 10.1002/1097-0142(19880515)61:10<2015::aid-cncr2820611014>3.0.co;2-z.
  84. Qi F, Sugihara T, Hattori Y, et al. Functional and morphological damage of endothelium in rabbit ear artery following irradiation with cobalt60. Br J Pharmacol. 1998; 123(4): 653–660.
  85. Hull MC, Morris CG, Pepine CJ, et al. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of hodgkin lymphoma treated with radiation therapy. JAMA. 2003; 290(21): 2831–2837.
  86. Campen CJ, Kranick SM, Kasner SE, et al. Cranial irradiation increases risk of stroke in pediatric brain tumor survivors. Stroke. 2012; 43(11): 3035–3040.
  87. Brant-Zawadzki M, Anderson M, DeArmond SJ, et al. Radiation-induced large intracranial vessel occlusive vasculopathy. AJR Am J Roentgenol. 1980; 134(1): 51–55.
  88. Beckman JA, Thakore A, Kalinowski BH, et al. Radiation therapy impairs endothelium-dependent vasodilation in humans. J Am Coll Cardiol. 2001; 37(3): 761–765.
  89. Meeske KA, Siegel SE, Gilsanz V, et al. Premature carotid artery disease in pediatric cancer survivors treated with neck irradiation. Pediatr Blood Cancer. 2009; 53(4): 615–621.
  90. Park KH, Park WJ. Endothelial Dysfunction: Clinical Implications in Cardiovascular Disease and Therapeutic Approaches. J Korean Med Sci. 2015; 30(9): 1213–1225.
  91. Jones LW, Fels DR, West M, et al. Modulation of circulating angiogenic factors and tumor biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy. Cancer Prev Res (Phila). 2013; 6(9): 925–937.
  92. Cadeddu C, Mercurio V, Spallarossa P, et al. Preventing antiblastic drug-related cardiomyopathy: old and new therapeutic strategies. J Cardiovasc Med (Hagerstown). 2016; 17 Suppl 1: S64–S75.
  93. Stojanović M, Radenković M. Vitamin D versus placebo in improvement of endothelial dysfunction: a meta-analysis of randomized clinical trials. Cardiovasc Ther. 2015; 33(3): 145–154.
  94. Mantell DJ, Owens PE, Bundred NJ, et al. 1 alpha,25-dihydroxyvitamin D(3) inhibits angiogenesis in vitro and in vivo. Circ Res. 2000; 87(3): 214–220.
  95. Heitzer T, Ylä Herttuala S, Wild E, et al. Effect of vitamin E on endothelial vasodilator function in patients with hypercholesterolemia, chronic smoking or both. J Am Coll Cardiol. 1999; 33(2): 499–505.
  96. Keaney J, Vita J. Atherosclerosis, oxidative stress, and antioxidant protection in endothelium-derived relaxing factor action. Prog Cardiovas Dis. 1995; 38(2): 129–154.
  97. Frcpe KY. Vitamin E in cardiovascular disease: has the die been cast? Asia Pacific J Clin Nutr. 2002; 11: 443–447.
  98. Hindler K, Cleeland CS, Rivera E, et al. The role of statins in cancer therapy. Oncologist. 2006; 11(3): 306–315.
  99. Cardinale D, Bacchiani G, Beggiato M, et al. Strategies to prevent and treat cardiovascular risk in cancer patients. Semin Oncol. 2013; 40(2): 186–198.
  100. Kalinowski L, Dobrucki LW, Szczepanska-Konkel M, et al. Third-generation beta-blockers stimulate nitric oxide release from endothelial cells through ATP efflux: a novel mechanism for antihypertensive action. Circulation. 2003; 107(21): 2747–2752.
  101. Rajagopalan S, Harrison DG. Reversing endothelial dysfunction with ACE inhibitors. A new trend. Circulation. 1996; 94(3): 240–243.
  102. Thakur A, Witteles RM. Cancer therapy-induced left ventricular dysfunction: interventions and prognosis. J Card Fail. 2014; 20(3): 155–158.
  103. Abdel-Rahman O, Alorabi M. Use of angiotensin-converting enzyme inhibitors in the prophylaxis of anthracycline or trastuzumab-related cardiac dysfunction: preclinical and clinical considerations. Expert Rev Anticancer Ther. 2015; 15(7): 829–837.
  104. Li X. ; 21(6): 1375–1383.
  105. Hartmann JT, Kollmannsberger C, Kanz L, et al. Platinum organ toxicity and possible prevention in patients with testicular cancer. Int J Cancer. 1999; 83(6): 866–869, doi: 10.1002/(sici)1097-0215(19991210)83:6<866::aid-ijc34>3.0.co;2-9.
  106. Räsänen M, Degerman J, Nissinen TA, et al. VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection. Proc Natl Acad Sci U S A. 2016; 113(46): 13144–13149.