Cardiotoxicity of antiangiogenic drugs: causes and mechanisms Review article
Article Sidebar
Published:
Mar 30, 2021
Keywords:
antiangiogenic agents, bevacizumab, cardiooncology, sorafenib, sunitinib
Main Article Content
Abstract
Therapy with angiogenesis inhibitors is undoubtedly an advancement in cancer treatment; however, it is associated with a risk of developing cardiotoxicity, which most often manifests in myocardial contractile dysfunction or an increased risk of thromboembolic events. Heart failure is observed in 2–4% of patients treated with bevacizumab and in 3–8% of patients on antiangiogenic tyrosine kinase inhibitors.
The proposed pathomechanisms underlying the impairment in systolic function during antiangiogenic drug treatment include mitochondrial dysfunction, a secondary reduction in cardiomyocyte ATP production and redox imbalance, which may contribute to pathological states known as “free radical diseases”. Additionally, therapy with angiogenesis inhibitors may also cause cardiac oxidative stress.
The risk factors for cardiac complications include arterial hypertension, which is a known “class effect” of this class of drugs, as well as a number of other factors such as age, comorbidities, prior radiotherapy and baseline left ventricular ejection fraction.
The cardiovascular diseases are still the first cause of death in the world. The more effective oncological treatment becomes, the more often comorbidities occur. This fact seems to demand interdisciplinary approach from investigators and practitioners.
This article presents the current state of knowledge on the molecular mechanisms of cardiotoxicity of antiangiogenic drugs used in routine clinical practice.
Downloads
Download data is not yet available.
Metrics
Metrics Loading ...
Article Details
How to Cite
1.
Tomaszewska B, Muzolf M, Grabysa R, Bodnar L. Cardiotoxicity of antiangiogenic drugs: causes and mechanisms. OncoReview [Internet]. 2021Mar.30 [cited 2024Dec.23];11(1(41):12-8. Available from: https://journalsmededu.pl/index.php/OncoReview/article/view/1228
Issue
Section
CARDIO-ONCOLOGY
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright: © Medical Education sp. z o.o. This is an Open Access article distributed under the terms of the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). License (https://creativecommons.org/licenses/by-nc/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Address reprint requests to: Medical Education, Marcin Kuźma (marcin.kuzma@mededu.pl)
References
1. Lenneman CG, Sawyer DB. Cardio-Oncology: An Update on Cardiotoxicity of Cancer-Related Treatment. Circ Res. 2016; 118(6): 1008-20.
2. Zamorano JL, Lancellotti P, Rodriguez Muńoz D et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016; 37(36): 2768-801.
3. Sawaya H, Sebag IA, Plana JC et al. Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol. 2011; 107(9): 1375-80.
4. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011; 11(6): 393-410.
5. Ferrara N, Adamis AP. Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov. 2016; 15(6): 385-403.
6. Rey S, Schito L, Wouters BG et al. Targeting Hypoxia-Inducible Factors for Antiangiogenic Cancer Therapy. Trends Cancer. 2017; 3(7): 529-41.
7. Eppler SM, Combs DL, Henry TD et al. A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans. Clin Pharmacol Ther. 2002; 72(1): 20-32.
8. Humphreys BD, Atkins MB. Rapid development of hypertension by sorafenib: toxicity or target? Clin Cancer Res. 2009; 15(19): 5947-9.
9. Chu TF, Rupnick MA, Kerkela R et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet Lond Engl. 2007; 370(9604): 2011-9.
10. Will Y, Dykens JA, Nadanaciva S et al. Effect of the multitargeted tyrosine kinase inhibitors imatinib, dasatinib, sunitinib, and sorafenib on mitochondrial function in isolated rat heart mitochondria and H9c2 cells. Toxicol Sci. 2008; 106(1): 153-61.
11. Imam F, Al-Harbi NO, Khan MR et al. Protective Effect of RIVA Against Sunitinib-Induced Cardiotoxicity by Inhibiting Oxidative Stress-Mediated Inflammation: Probable Role of TGF-β and Smad Signaling. Cardiovasc Toxicol. 2020; 20(3): 281-90.
12. Izumiya Y, Shiojima I, Sato K et al. Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload. Hypertens Dallas Tex. 1979. 2006; 47(5): 887-93.
13. Chintalgattu V, Ai D, Langley RR et al. Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress. J Clin Invest. 2010; 120(2): 472-84.
14. Gupta R, Maitland ML. Sunitinib, hypertension, and heart failure: a model for kinase inhibitor-mediated cardiotoxicity. Curr Hypertens Rep. 2011; 13(6): 430-5.
15. Szmit S. The cardiac safety during treatment with sunitinib and sorafenib, multikinase angiogenesis inhibitors. OncoReview. 2012; 2(6): 134-42.
16. Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007; 7(5): 332-44.
17. Khakoo AY , Kassiotis CM, Tannir N et al. Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. Cancer. 2008; 112(11): 2500-8.
18. Garcipérez de Vargas FJ, Gómez-Barrado JJ, Ortiz C et al. [Refractory heart failure in a patient treated with bevacizumab]. Med Intensiva. 2012; 36(8): 589-90.
19. Hawkes EA, Okines AFC, Plummer C et al. Cardiotoxicity in patients treated with bevacizumab is potentially reversible. J Clin Oncol. 2011; 29(18): e560-2.
20. Szmit S, Nurzyński P, Szaluś N et al. Reversible myocardial dysfunction in a young woman with metastatic renal cell carcinoma treated with sunitinib. Acta Oncol Stockh Swed. 2009; 48(6): 921-5.
21. Schmidinger M, Zielinski CC, Vogl UM et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2008; 26(32): 5204-12.
22. Kuenen BC, Levi M, Meijers JCM et al. Analysis of coagulation cascade and endothelial cell activation during inhibition of vascular endothelial growth factor/vascular endothelial growth factor receptor pathway in cancer patients. Arterioscler Thromb Vasc Biol. 2002; 22(9): 1500-5.
23. Economopoulou P, Kotsakis A, Kapiris I et al. Cancer therapy and cardiovascular risk: focus on bevacizumab. Cancer Manag Res. 2015; 7: 133-43.
24. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007; 356(2): 125-34.
25. Ravaud A, Motzer RJ, Pandha HS et al; S-TRAC Investigators. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med. 2016; 375(23): 2246-54.
26. Justice CN, Derbala MH, Baich TM et al. The Impact of Pazopanib on the Cardiovascular System. J Cardiovasc Pharmacol Ther. 2018; 23(5): 387-98.
27. Grande E, Kreissl MC, Filetti S et al. Vandetanib in advanced medullary thyroid cancer: review of adverse event management strategies. Adv Ther. 2013; 30(11): 945-66.
28. Bonaldo G, Vaccheri A, Melis M, Motola D. Drug-induced disseminated intravascular coagulation: a pharmacovigilance study on World Health Organization’s database. J Thromb Thrombolysis. 2020; 50(4): 763-71.
29. Choueiri TK, Hessel C, Halabi S et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression free survival by independent review and overall survival update. Eur J Cancer. 2018; 94: 115-25.
30. Wilke H, Muro K, Van Cutsem E et al; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014; 15(11): 1224-35.
31. Kudo M, Finn RS, Qin S et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018; 391(10126): 1163-73.
32. Rini BI, Escudier B, Tomczak P et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011; 378(9807): 1931-9.
33. Reck M, Kaiser R, Mellemgaard A; LUME-Lung 1 Study Group. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014; 15(2): 143-55.
34. Pantaleo MA, Mandrioli A, Saponara M et al. Development of coronary artery stenosis in a patient with metastatic renal cell carcinoma treated with sorafenib. BMC Cancer. 2012; 12: 231.
35. Habib M, Czernek U, Dębska S et al. Ostry zespół wieńcowy w trakcie leczenia sorafenibem – opis chorej. Oncol Clin Pract. 2012; 8(3): 124-7.
36. Abdel-Qadir H, Ethier J-L, Lee DS et al. Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: A systematic review and meta-analysis. Cancer Treat Rev. 2017; 53: 120-7.
37. Bello CL, Mulay M, Huang X et al. Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic – pharmacodynamic evaluation of sunitinib. Clin Cancer Res. 2009; 15(22): 7045-52.
38. Ghatalia P, Je Y, Kaymakcalan MD et al. QTc interval prolongation with vascular endothelial growth factor receptor tyrosine kinase inhibitors. Br J Cancer. 2015; 112(2): 296-305.
39. Sanguinetti MC, Mitcheson JS. Predicting drug-hERG channel interactions that cause acquired long QT syndrome. Trends Pharmacol Sci. 2005; 26(3): 119-24.
40. Obers S, Staudacher I, Ficker E et al. Multiple mechanisms of hERG liability: K+ current inhibition, disruption of protein trafficking, and apoptosis induced by amoxapine. Naunyn Schmiedebergs Arch Pharmacol. 2010; 381(5): 385-400.
41. Dennis AT, Wang L, Wan H et al. Molecular determinants of pentamidine-induced hERG trafficking inhibition. Mol Pharmacol. 2012; 81(2): 198-209.
2. Zamorano JL, Lancellotti P, Rodriguez Muńoz D et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016; 37(36): 2768-801.
3. Sawaya H, Sebag IA, Plana JC et al. Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol. 2011; 107(9): 1375-80.
4. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011; 11(6): 393-410.
5. Ferrara N, Adamis AP. Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov. 2016; 15(6): 385-403.
6. Rey S, Schito L, Wouters BG et al. Targeting Hypoxia-Inducible Factors for Antiangiogenic Cancer Therapy. Trends Cancer. 2017; 3(7): 529-41.
7. Eppler SM, Combs DL, Henry TD et al. A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans. Clin Pharmacol Ther. 2002; 72(1): 20-32.
8. Humphreys BD, Atkins MB. Rapid development of hypertension by sorafenib: toxicity or target? Clin Cancer Res. 2009; 15(19): 5947-9.
9. Chu TF, Rupnick MA, Kerkela R et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet Lond Engl. 2007; 370(9604): 2011-9.
10. Will Y, Dykens JA, Nadanaciva S et al. Effect of the multitargeted tyrosine kinase inhibitors imatinib, dasatinib, sunitinib, and sorafenib on mitochondrial function in isolated rat heart mitochondria and H9c2 cells. Toxicol Sci. 2008; 106(1): 153-61.
11. Imam F, Al-Harbi NO, Khan MR et al. Protective Effect of RIVA Against Sunitinib-Induced Cardiotoxicity by Inhibiting Oxidative Stress-Mediated Inflammation: Probable Role of TGF-β and Smad Signaling. Cardiovasc Toxicol. 2020; 20(3): 281-90.
12. Izumiya Y, Shiojima I, Sato K et al. Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload. Hypertens Dallas Tex. 1979. 2006; 47(5): 887-93.
13. Chintalgattu V, Ai D, Langley RR et al. Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress. J Clin Invest. 2010; 120(2): 472-84.
14. Gupta R, Maitland ML. Sunitinib, hypertension, and heart failure: a model for kinase inhibitor-mediated cardiotoxicity. Curr Hypertens Rep. 2011; 13(6): 430-5.
15. Szmit S. The cardiac safety during treatment with sunitinib and sorafenib, multikinase angiogenesis inhibitors. OncoReview. 2012; 2(6): 134-42.
16. Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007; 7(5): 332-44.
17. Khakoo AY , Kassiotis CM, Tannir N et al. Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. Cancer. 2008; 112(11): 2500-8.
18. Garcipérez de Vargas FJ, Gómez-Barrado JJ, Ortiz C et al. [Refractory heart failure in a patient treated with bevacizumab]. Med Intensiva. 2012; 36(8): 589-90.
19. Hawkes EA, Okines AFC, Plummer C et al. Cardiotoxicity in patients treated with bevacizumab is potentially reversible. J Clin Oncol. 2011; 29(18): e560-2.
20. Szmit S, Nurzyński P, Szaluś N et al. Reversible myocardial dysfunction in a young woman with metastatic renal cell carcinoma treated with sunitinib. Acta Oncol Stockh Swed. 2009; 48(6): 921-5.
21. Schmidinger M, Zielinski CC, Vogl UM et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2008; 26(32): 5204-12.
22. Kuenen BC, Levi M, Meijers JCM et al. Analysis of coagulation cascade and endothelial cell activation during inhibition of vascular endothelial growth factor/vascular endothelial growth factor receptor pathway in cancer patients. Arterioscler Thromb Vasc Biol. 2002; 22(9): 1500-5.
23. Economopoulou P, Kotsakis A, Kapiris I et al. Cancer therapy and cardiovascular risk: focus on bevacizumab. Cancer Manag Res. 2015; 7: 133-43.
24. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007; 356(2): 125-34.
25. Ravaud A, Motzer RJ, Pandha HS et al; S-TRAC Investigators. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med. 2016; 375(23): 2246-54.
26. Justice CN, Derbala MH, Baich TM et al. The Impact of Pazopanib on the Cardiovascular System. J Cardiovasc Pharmacol Ther. 2018; 23(5): 387-98.
27. Grande E, Kreissl MC, Filetti S et al. Vandetanib in advanced medullary thyroid cancer: review of adverse event management strategies. Adv Ther. 2013; 30(11): 945-66.
28. Bonaldo G, Vaccheri A, Melis M, Motola D. Drug-induced disseminated intravascular coagulation: a pharmacovigilance study on World Health Organization’s database. J Thromb Thrombolysis. 2020; 50(4): 763-71.
29. Choueiri TK, Hessel C, Halabi S et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression free survival by independent review and overall survival update. Eur J Cancer. 2018; 94: 115-25.
30. Wilke H, Muro K, Van Cutsem E et al; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014; 15(11): 1224-35.
31. Kudo M, Finn RS, Qin S et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018; 391(10126): 1163-73.
32. Rini BI, Escudier B, Tomczak P et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011; 378(9807): 1931-9.
33. Reck M, Kaiser R, Mellemgaard A; LUME-Lung 1 Study Group. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014; 15(2): 143-55.
34. Pantaleo MA, Mandrioli A, Saponara M et al. Development of coronary artery stenosis in a patient with metastatic renal cell carcinoma treated with sorafenib. BMC Cancer. 2012; 12: 231.
35. Habib M, Czernek U, Dębska S et al. Ostry zespół wieńcowy w trakcie leczenia sorafenibem – opis chorej. Oncol Clin Pract. 2012; 8(3): 124-7.
36. Abdel-Qadir H, Ethier J-L, Lee DS et al. Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: A systematic review and meta-analysis. Cancer Treat Rev. 2017; 53: 120-7.
37. Bello CL, Mulay M, Huang X et al. Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic – pharmacodynamic evaluation of sunitinib. Clin Cancer Res. 2009; 15(22): 7045-52.
38. Ghatalia P, Je Y, Kaymakcalan MD et al. QTc interval prolongation with vascular endothelial growth factor receptor tyrosine kinase inhibitors. Br J Cancer. 2015; 112(2): 296-305.
39. Sanguinetti MC, Mitcheson JS. Predicting drug-hERG channel interactions that cause acquired long QT syndrome. Trends Pharmacol Sci. 2005; 26(3): 119-24.
40. Obers S, Staudacher I, Ficker E et al. Multiple mechanisms of hERG liability: K+ current inhibition, disruption of protein trafficking, and apoptosis induced by amoxapine. Naunyn Schmiedebergs Arch Pharmacol. 2010; 381(5): 385-400.
41. Dennis AT, Wang L, Wan H et al. Molecular determinants of pentamidine-induced hERG trafficking inhibition. Mol Pharmacol. 2012; 81(2): 198-209.