Skip to main content

Advertisement

SpringerLink
Log in

Sunitinib does not acutely alter left ventricular systolic function, but induces diastolic dysfunction

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Cancer chemotherapies have improved the prognosis of cancer patients in recent years; however, their side effects on the cardiovascular systems have emerged as a major concern in the field of both cardiology and oncology. In particular, multi-targeted tyrosine kinase inhibitors are known to induce various types of cardiovascular adverse events including hypertension, QT-interval prolongation and heart failure, but their underlying mechanisms remain elusive. To explore how to better predict such drug-induced cardiovascular adverse events, we assessed the electropharmacological effects of sunitinib using the halothane-anesthetized dogs (n = 5), while plasma concentrations of cardiac enzymes including aspartate aminotransferase, lactate dehydrogenase, creatinine kinase and cardiac troponin I  were measured.

Methods

Sunitinib was intravenously administered at 0.01 and 0.1 mg/kg for 10 min with 20 min interval.

Results

Sunitinib decreased the amplitude of maximum downstroke velocity of the left ventricular pressure, prolonged the isovolumic relaxation time and increased the left ventricular end-diastolic pressure in a dose-related manner without affecting the other cardiohemodynamic and electrophysiological variables. More importantly, sunitinib significantly elevated cardiac troponin I level for 30–60 min after the high dose without altering the other biomarkers.

Conclusions

Monitoring of the cardiac diastolic function together with cardiac troponin I after the start of sunitinib administration may become a reliable measure to predict the onset of sunitinib-induced cardiovascular adverse events.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, Habib G, Lenihan DJ, Lip GY, Lyon AR, Lopez Fernandez T, Mohty D, Piepoli MF, Tamargo J, Torbicki A, Suter TM (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 37:2768–2801

    Article  PubMed  Google Scholar 

  2. Cautela J, Lalevée N, Ammar C, Ederhy S, Peyrol M, Debourdeau P, Serin D, Le Dolley Y, Michel N, Orabona M, Barraud J, Laine M, Bonello L, Paganelli F, Barlési F, Thuny F (2016) Management and research in cancer treatment-related cardiovascular toxicity: challenges and perspectives. Int J Cardiol 224:366–375

    Article  PubMed  Google Scholar 

  3. Henson KE, Reulen RC, Winter DL, Bright CJ, Fidler MM, Frobisher C, Guha J, Wong KF, Kelly J, Edgar AB, McCabe MG, Whelan J, Cutter DJ, Darby SC, Hawkins MM (2016) Cardiac mortality among 200 000 five-year survivors of cancer diagnosed at 15 to 39 years of age: the teenage and young adult cancer survivor study. Circulation 134:1519–1531

    Article  PubMed  PubMed Central  Google Scholar 

  4. Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM (2010) Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst 102:14–25

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Krause DS, Van Etten RA (2005) Tyrosine kinases as targets for cancer therapy. N Engl J Med 353:172–187

    Article  PubMed  CAS  Google Scholar 

  6. Blumenthal GM, Cortazar P, Zhang JJ, Tang S, Sridhara R, Murgo A, Justice R, Pazdur R (2012) FDA approval summary: sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors. Oncologist 17:1108–1113

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9:327–337

    PubMed  CAS  Google Scholar 

  8. Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L, Woulfe K, Pravda E, Cassiola F, Desai J, George S, Morgan JA, Harris DM, Ismail NS, Chen JH, Schoen FJ, Van den Abbeele AD, Demetri GD, Force T, Chen MH (2007) Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370:2011–2019

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Force T, Krause DS, Van Etten RA (2007) Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 7:332–344

    Article  PubMed  CAS  Google Scholar 

  10. Hasinoff BB, Patel D, O’Hara KA (2008) Mechanisms of myocyte cytotoxicity induced by the multiple receptor tyrosine kinase inhibitor sunitinib. Mol Pharmacol 74:1722–1728

    Article  PubMed  CAS  Google Scholar 

  11. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA (2009) Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 27:3584–3590

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Akaza H, Naito S, Ueno N, Aoki K, Houzawa H, Pitman Lowenthal S, Lee SY (2015) Real-world use of sunitinib in Japanese patients with advanced renal cell carcinoma: efficacy, safety and biomarker analyses in 1689 consecutive patients. Jpn J Clin Oncol 45:576–583

    Article  PubMed  PubMed Central  Google Scholar 

  13. Vrdoljak E, Géczi L, Mardiak J, Ciuleanu TE, Leyman S, Zhang K, Sajben P, Torday L (2015) Central and eastern european experience with sunitinib in metastatic renal cell carcinoma: a sub-analysis of the global expanded-access trial. Pathol Oncol Res 21:775–782

    Article  PubMed  CAS  Google Scholar 

  14. Sugiyama A (2008) Sensitive and reliable proarrhythmia in vivo animal models for predicting drug-induced torsade de pointes in patients with remodelled hearts. Br J Pharmacol 154:1528–1537

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Sugiyama A, Hashimoto K (1998) Effects of gastrointestinal prokinetic agents, TKS159 and cisapride, on the in situ canine heart assessed by cardiohemodynamic and electrophysiological monitoring. Toxicol Appl Pharmacol 152:261–269

    Article  PubMed  CAS  Google Scholar 

  16. Qi WX, Shen Z, Tang LN, Yao Y (2014) Congestive heart failure risk in cancer patients treated with vascular endothelial growth factor tyrosine kinase inhibitors: a systematic review and meta-analysis of 36 clinical trials. Br J Clin Pharmacol 78:748–762

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Bordun KA, Premecz S, daSilva M, Mandal S, Goyal V, Glavinovic T, Cheung M, Cheung D, White CW, Chaudhary R, Freed DH, Villarraga HR, Herrmann J, Kohli M, Ravandi A, Thliveris J, Pitz M, Singal PK, Mulvagh S, Jassal DS (2015) The utility of cardiac biomarkers and echocardiography for the early detection of bevacizumab- and sunitinib-mediated cardiotoxicity. Am J Physiol Heart Circ Physiol 309:H692-701

    Article  PubMed  CAS  Google Scholar 

  18. Nikolić S, Yellin EL, Tamura K, Vetter H, Tamura T, Meisner JS, Frater RW (1988) Passive properties of canine left ventricle: diastolic stiffness and restoring forces. Circ Res 62:1210–1222

    Article  PubMed  Google Scholar 

  19. Van de Water A, Verheyen J, Xhonneux R, Reneman RS (1989) An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. J Pharmacol Methods 22:207–217

    Article  PubMed  Google Scholar 

  20. Teichholz LE, Kreulen T, Herman MV, Gorlin R (1976) Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in the presence of absence of asynergy. Am J Cardiol 37:7–11

    Article  PubMed  CAS  Google Scholar 

  21. Otto CM (2004) Left and right ventricular systolic function. In: Otto CM (ed) Textbook of clinical echocardiography, 3rd edn. Elsevier Saunders, Philadelphia, pp 131–165

    Google Scholar 

  22. Pai RG, Gill KS (1998) Amplitudes, durations, and timings of apically directed left ventricular myocardial velocities: II. Systolic and diastolic asynchrony in patients with left ventricular hypertrophy. J Am Soc Echocardiogr 11:112–118

    Article  PubMed  CAS  Google Scholar 

  23. Blanchet B, Saboureau C, Benichou AS, Billemont B, Taieb F, Ropert S, Dauphin A, Goldwasser F, Tod M (2009) Development and validation of an HPLC-UV-visible method for sunitinib quantification in human plasma. Clin Chim Acta 404:134–139

    Article  PubMed  CAS  Google Scholar 

  24. Yang Y, Bu P (2016) Progress on the cardiotoxicity of sunitinib: Prognostic significance, mechanism and protective therapies. Chem Biol Interact 257:125–131

    Article  PubMed  CAS  Google Scholar 

  25. León-Mateos L, Mosquera J, Antón Aparicio L (2015) Treatment of sunitinib-induced hypertension in solid tumor by nitric oxide donors. Redox Biol 6:421–425

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Azizi M, Chedid A, Oudard S (2008) Home blood-pressure monitoring in patients receiving sunitinib. N Engl J Med 358:95–97

    Article  PubMed  CAS  Google Scholar 

  27. Khakoo AY, Kassiotis CM, Tannir N, Plana JC, Halushka M, Bickford C, Trent J II, Champion JC, Durand JB, Lenihan DJ (2008) Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. Cancer 112:2500–2508

    Article  PubMed  CAS  Google Scholar 

  28. Deeks ED, Keating GM (2006) Sunitinib. Drugs 66:2255–2266

    Article  PubMed  CAS  Google Scholar 

  29. Kerkela R, Woulfe KC, Durand JB, Vagnozzi R, Kramer D, Chu TF, Beahm C, Chen MH, Force T (2009) Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. Clin Transl Sci 2:15–25

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Doherty KR, Wappel RL, Talbert DR, Trusk PB, Moran DM, Kramer JW, Brown AM, Shell SA, Bacus S (2013) Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes. Toxicol Appl Pharmacol 272:245–255

    Article  PubMed  CAS  Google Scholar 

  31. Thijs AM, El Messaoudi S, Vos JC, Wouterse AC, Verweij V, van Swieten H, van Herpen CM, van der Graaf WT, Noyez L, Rongen GA (2015) Sunitinib does not attenuate contractile force following a period of ischemia in isolated human cardiac muscle. Target Oncol 10:439–443

    Article  PubMed  Google Scholar 

  32. Oyama MA, Sisson DD (2004) Cardiac troponin-I concentration in dogs with cardiac disease. J Vet Intern Med 18:831–839

    Article  PubMed  Google Scholar 

  33. Katz AM (1988) Cellular mechanisms in congestive heart failure. Am J Cardiol 62:3A-8A

    Article  PubMed  Google Scholar 

  34. Mooney L, Skinner M, Coker SJ, Currie S (2015) Effects of acute and chronic sunitinib treatment on cardiac function and calcium/calmodulin-dependent protein kinase II. Br J Pharmacol 172:4342–4354

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Ghatalia P, Je Y, Kaymakcalan MD, Sonpavde G, Choueiri TK (2015) QTc interval prolongation with vascular endothelial growth factor receptor tyrosine kinase inhibitors. Br J Cancer 112:296–305

    Article  PubMed  CAS  Google Scholar 

  36. Bello CL, Mulay M, Huang X, Patyna S, Dinolfo M, Levine S, Van Vugt A, Toh M, Baum C, Rosen L (2009) Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic–pharmacodynamic evaluation of sunitinib. Clin Cancer Res 15:7045–7052

    Article  PubMed  CAS  Google Scholar 

  37. Näbauer M, Kääb S (1998) Potassium channel down-regulation in heart failure. Cardiovasc Res 37:324–334

    Article  PubMed  Google Scholar 

  38. Strevel EL, Ing DJ, Siu LL (2007) Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol 25:3362–3371

    Article  PubMed  CAS  Google Scholar 

  39. Bowlin SJ, Xia F, Wang W, Robinson KD, Stanek EJ (2013) Twelve-month frequency of drug-metabolizing enzyme and transporter-based drug–drug interaction potential in patients receiving oral enzyme-targeted kinase inhibitor antineoplastic agents. Mayo Clin Proc 88:139–148

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported in part by the Fund for the Advancement of Science in commemoration of Toho University’s 60th anniversary and JSPS KAKENHI (#JP15K08246, #JP16K08559, #JP17K17068). The authors thank Ms. Misako Nakatani and Mrs. Yuri Ichikawa for their technical assistance.

Funding

This study was funded in part by the Fund for the Advancement of Science in commemoration of Toho University’s 60th anniversary and JSPS KAKENHI (#JP15K08246, #JP16K08559, #JP17K17068).

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan

    Takeshi Wada, Kentaro Ando, Atsuhiko T. Naito, Yuji Nakamura, Mihoko Hagiwara-Nagasawa, Hiroko Izumi-Nakaseko & Atsushi Sugiyama

  2. Department of Cardiology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba, 279-0021, Japan

    Takeshi Wada & Yuji Nakazato

  3. Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan

    Kentaro Ando, Atsuhiko T. Naito, Ai Goto, Koki Chiba, Nur Jaharat Lubna & Atsushi Sugiyama

  4. Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba, 274-8510, Japan

    Xin Cao

Authors
  1. Takeshi Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kentaro Ando
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Atsuhiko T. Naito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuji Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ai Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Koki Chiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nur Jaharat Lubna
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xin Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mihoko Hagiwara-Nagasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hiroko Izumi-Nakaseko
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yuji Nakazato
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Atsushi Sugiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Atsushi Sugiyama.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Ethical approval

All experiments were approved by Toho University Animal Care and User Committee (nos. 15-55-151, 15-52-272, 16-51-324, 16-53-272) and performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of Toho University.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wada, T., Ando, K., Naito, A.T. et al. Sunitinib does not acutely alter left ventricular systolic function, but induces diastolic dysfunction. Cancer Chemother Pharmacol 82, 65–75 (2018). https://doi.org/10.1007/s00280-018-3593-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-018-3593-9

Keywords

Search

Navigation