Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 77, Issue 4, pp 777–785 | Cite as

Overweight in mice, induced by perinatal programming, exacerbates doxorubicin and trastuzumab cardiotoxicity

  • Charles Guenancia
  • Olivier Hachet
  • Mona Aboutabl
  • Na Li
  • Eve Rigal
  • Yves Cottin
  • Luc Rochette
  • Catherine Vergely
Original Article

Abstract

Purpose

Trastuzumab (TRZ) is believed to potentiate doxorubicin (DOX) cardiotoxicity, resulting in left ventricular dysfunction. There is some evidence that overweight could influence anticancer drug-induced cardiotoxicity, though no study has evaluated the impact of moderate overweight, induced by postnatal nutritional programming, on the cardiotoxic effects of DOX alone or in combination with TRZ.

Methods

Immediately after birth, litters of C57BL/6 mice were either maintained at 9 pups (normal litter, NL) or reduced to 3 (small litter, SL) in order to induce programming of ~15 % overweight through postnatal overfeeding. At 4 months, NL and SL mice received a single intra-peritoneal injection of either saline, DOX (6 mg/kg), TRZ (10 mg/kg) or both (DOX–TRZ). Transthoracic echocardiography was performed 24 h before as well as 10 and 20 days after treatments.

Results

Twenty days after DOX administration, systolic dysfunction was observed only in the overweight SL group, while NL mice group had a normal left ventricular ejection fraction. However, in the NL group, functional impairment appeared when TRZ was co-administered. Forty-eight hours after drug administration, gene expression of natriuretic peptides (ANP, BNP) appeared to be potentiated in DOX–TRZ mice of both the NL and SL group, whereas the expression of β-MHC increased significantly in overweight SL mice only.

Conclusions

In an acute model of DOX cardiotoxicity, moderately overweight adult mice were more sensitive to cardiac systolic impairment. Moreover, our results confirm the potentiating action of TRZ on DOX-induced cardiotoxicity in lean mice.

Keywords

Doxorubicin Trastuzumab Cardiotoxicity Overweight Postnatal programming 

Notes

Acknowledgments

The authors thank Françoise Bechet for technical assistance and Mr. Philip Bastable for English revision of the manuscript.

Funding

This work was supported by grants from the French Ministry of Research, the Institut National de la Santé et de la Recherche Médicale (INSERM), the Société Française de Cardiologie (SFC), the Regional Council of Burgundy, the Association de Cardiologie de Bourgogne (ACB) and the French Government through a fellowship granted by the French Embassy in Egypt (Institut Français d’Egypte).

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest including financial and personal relationships with other people or organizations that could inappropriately influence this work.

References

  1. 1.
    Pommier Y, Leo E, Zhang H, Marchand C (2010) DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol 17(5):421–433. doi: 10.1016/j.chembiol.2010.04.012 CrossRefPubMedGoogle Scholar
  2. 2.
    Singal PK, Iliskovic N (1998) Doxorubicin-induced cardiomyopathy. N Engl J Med 339(13):900–905. doi: 10.1056/NEJM199809243391307 CrossRefPubMedGoogle Scholar
  3. 3.
    Keefe DL (2001) Anthracycline-induced cardiomyopathy. Semin Oncol 28(4 Suppl 12):2–7CrossRefPubMedGoogle Scholar
  4. 4.
    Shepard HM, Lewis GD, Sarup JC, Fendly BM, Maneval D, Mordenti J, Figari I, Kotts CE, Palladino MA Jr, Ullrich A et al (1991) Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic. J Clin Immunol 11(3):117–127CrossRefPubMedGoogle Scholar
  5. 5.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792. doi: 10.1056/NEJM200103153441101 CrossRefPubMedGoogle Scholar
  6. 6.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Lang I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Ruschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD, Herceptin Adjuvant Trial Study T (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353 (16):1659–1672. doi: 10.1056/NEJMoa052306
  7. 7.
    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353(16):1673–1684. doi: 10.1056/NEJMoa052122 CrossRefPubMedGoogle Scholar
  8. 8.
    Dawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH (2010) Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol 28(1):92–98. doi: 10.1200/JCO.2008.19.9844 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Klein PM, Dybdal N (2003) Trastuzumab and cardiac dysfunction: update on preclinical studies. Semin Oncol 30(5 Suppl 16):49–53CrossRefPubMedGoogle Scholar
  10. 10.
    Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D (2002) Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20(5):1215–1221CrossRefPubMedGoogle Scholar
  11. 11.
    Perez EA, Rodeheffer R (2004) Clinical cardiac tolerability of trastuzumab. J Clin Oncol 22(2):322–329. doi: 10.1200/JCO.2004.01.120 CrossRefPubMedGoogle Scholar
  12. 12.
    Jahanzeb M (2008) Adjuvant trastuzumab therapy for HER2-positive breast cancer. Clin Breast Cancer 8(4):324–333. doi: 10.3816/CBC.2008.n.037 CrossRefPubMedGoogle Scholar
  13. 13.
    Fedele C, Riccio G, Coppola C, Barbieri A, Monti MG, Arra C, Tocchetti CG, D’Alessio G, Maurea N, De Lorenzo C (2012) Comparison of preclinical cardiotoxic effects of different ErbB2 inhibitors. Breast Cancer Res Treat 133(2):511–521. doi: 10.1007/s10549-011-1783-9 CrossRefPubMedGoogle Scholar
  14. 14.
    Jassal DS, Han SY, Hans C, Sharma A, Fang T, Ahmadie R, Lytwyn M, Walker JR, Bhalla RS, Czarnecki A, Moussa T, Singal PK (2009) Utility of tissue Doppler and strain rate imaging in the early detection of trastuzumab and anthracycline mediated cardiomyopathy. J Am Soc Echocardiogr 22(4):418–424. doi: 10.1016/j.echo.2009.01.016 CrossRefPubMedGoogle Scholar
  15. 15.
    Riccio G, Esposito G, Leoncini E, Contu R, Condorelli G, Chiariello M, Laccetti P, Hrelia S, D’Alessio G, De Lorenzo C (2009) Cardiotoxic effects, or lack thereof, of anti-ErbB2 immunoagents. FASEB J 23(9):3171–3178. doi: 10.1096/fj.09-131383 CrossRefPubMedGoogle Scholar
  16. 16.
    Gordon LI, Burke MA, Singh AT, Prachand S, Lieberman ED, Sun L, Naik TJ, Prasad SV, Ardehali H (2009) Blockade of the erbB2 receptor induces cardiomyocyte death through mitochondrial and reactive oxygen species-dependent pathways. J Biol Chem 284(4):2080–2087. doi: 10.1074/jbc.M804570200 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rochette L, Guenancia C, Gudjoncik A, Hachet O, Zeller M, Cottin Y, Vergely C (2015) Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms. Trends Pharmacol Sci 36(6):326–348. doi: 10.1016/j.tips.2015.03.005 CrossRefPubMedGoogle Scholar
  18. 18.
    De Pergola G, Silvestris F (2013) Obesity as a major risk factor for cancer. J Obes 2013:291546. doi: 10.1155/2013/291546 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Zeller M, Steg PG, Ravisy J, Lorgis L, Laurent Y, Sicard P, Janin-Manificat L, Beer JC, Makki H, Lagrost AC, Rochette L, Cottin Y, Group RSW (2008) Relation between body mass index, waist circumference, and death after acute myocardial infarction. Circulation 118(5):482–490. doi: 10.1161/CIRCULATIONAHA.107.753483 CrossRefPubMedGoogle Scholar
  20. 20.
    Rodvold KA, Rushing DA, Tewksbury DA (1988) Doxorubicin clearance in the obese. J Clin Oncol 6(8):1321–1327PubMedGoogle Scholar
  21. 21.
    Mitra MS, Donthamsetty S, White B, Mehendale HM (2008) High fat diet-fed obese rats are highly sensitive to doxorubicin-induced cardiotoxicity. Toxicol Appl Pharmacol 231(3):413–422. doi: 10.1016/j.taap.2008.05.006 CrossRefPubMedGoogle Scholar
  22. 22.
    de Azambuja E, McCaskill-Stevens W, Francis P, Quinaux E, Crown JP, Vicente M, Giuliani R, Nordenskjold B, Gutierez J, Andersson M, Vila MM, Jakesz R, Demol J, Dewar J, Santoro A, Lluch A, Olsen S, Gelber RD, Di Leo A, Piccart-Gebhart M (2010) The effect of body mass index on overall and disease-free survival in node-positive breast cancer patients treated with docetaxel and doxorubicin-containing adjuvant chemotherapy: the experience of the BIG 02-98 trial. Breast Cancer Res Treat 119(1):145–153. doi: 10.1007/s10549-009-0512-0 CrossRefPubMedGoogle Scholar
  23. 23.
    Ryu SY, Kim CB, Nam CM, Park JK, Kim KS, Park J, Yoo SY, Cho KS (2001) Is body mass index the prognostic factor in breast cancer? A meta-analysis. J Korean Med Sci 16(5):610–614CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Habbout A, Li N, Rochette L, Vergely C (2013) Postnatal overfeeding in rodents by litter size reduction induces major short- and long-term pathophysiological consequences. J Nutr 143(5):553–562. doi: 10.3945/jn.112.172825 CrossRefPubMedGoogle Scholar
  25. 25.
    Habbout A, Guenancia C, Lorin J, Rigal E, Fassot C, Rochette L, Vergely C (2013) Postnatal overfeeding causes early shifts in gene expression in the heart and long-term alterations in cardiometabolic and oxidative parameters. PLoS One 8(2):e56981. doi: 10.1371/journal.pone.0056981 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Habbout A, Delemasure S, Goirand F, Guilland JC, Chabod F, Sediki M, Rochette L, Vergely C (2012) Postnatal overfeeding in rats leads to moderate overweight and to cardiometabolic and oxidative alterations in adulthood. Biochimie 94(1):117–124. doi: 10.1016/j.biochi.2011.09.023 CrossRefPubMedGoogle Scholar
  27. 27.
    Walker JR, Sharma A, Lytwyn M, Bohonis S, Thliveris J, Singal PK, Jassal DS (2011) The cardioprotective role of probucol against anthracycline and trastuzumab-mediated cardiotoxicity. J Am Soc Echocardiogr 24(6):699–705. doi: 10.1016/j.echo.2011.01.018 CrossRefPubMedGoogle Scholar
  28. 28.
    Milano G, Raucci A, Scopece A, Daniele R, Guerrini U, Sironi L, Cardinale D, Capogrossi MC, Pompilio G (2014) Doxorubicin and trastuzumab regimen induces biventricular failure in mice. J Am Soc Echocardiogr 27(5):568–579. doi: 10.1016/j.echo.2014.01.014 CrossRefPubMedGoogle Scholar
  29. 29.
    Guenancia C, Li N, Hachet O, Rigal E, Cottin Y, Dutartre P, Rochette L, Vergely C (2015) Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice. Toxicol Appl Pharmacol 284(2):152–162. doi: 10.1016/j.taap.2015.02.015 CrossRefPubMedGoogle Scholar
  30. 30.
    Parekh N, Chandran U, Bandera EV (2012) Obesity in cancer survival. Annu Rev Nutr 32:311–342. doi: 10.1146/annurev-nutr-071811-150713 CrossRefPubMedGoogle Scholar
  31. 31.
    Zeglinski M, Ludke A, Jassal DS, Singal PK (2011) Trastuzumab-induced cardiac dysfunction: a ‘dual-hit’. Exp Clin Cardiol 16(3):70–74PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Charles Guenancia
    • 1
    • 2
  • Olivier Hachet
    • 1
    • 2
  • Mona Aboutabl
    • 1
    • 3
  • Na Li
    • 1
  • Eve Rigal
    • 1
  • Yves Cottin
    • 1
    • 2
  • Luc Rochette
    • 1
  • Catherine Vergely
    • 1
  1. 1.Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (LPPCM), Inserm UMR866, Faculties of Health SciencesUniversity of Bourgogne-Franche-ComteDijonFrance
  2. 2.Cardiology DepartmentUniversity HospitalDijonFrance
  3. 3.Pharmacology Group, Medicinal and Pharmaceutical Chemistry DepartmentPharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618)GizaEgypt

Personalised recommendations