© 1999 American Heart Association, Inc.
Original Contribution |
Daunorubicin-Induced Apoptosis in Rat Cardiac Myocytes Is Inhibited by Dexrazoxane
From the Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. The current affiliation for Dr Sawyer is Cardiology Division, Boston University Medical Center, Boston, Mass. The current affiliation for Dr Arstall is Cardiology Unit, The Queen Elizabeth Hospital, Woodville, South Australia.
Correspondence to Ralph A. Kelly, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail rakelly{at}rics.bwh.harvard.edu
Abstract—The clinical efficacy
of anthracycline antineoplastic agents is limited by a high incidence
of severe and usually irreversible cardiac toxicity, the cause of which
remains controversial. In primary cultures of neonatal and adult rat
ventricular myocytes, we found that daunorubicin, at
concentrations 
1 µmol/L, induced myocyte programmed cell death
within 24 hours, as defined by several complementary techniques. In
contrast, daunorubicin concentrations 
10 µmol/L induced
necrotic cell death within 24 hours, with no changes characteristic of
apoptosis. To determine whether reactive oxygen species play a
role in daunorubicin-mediated apoptosis, we monitored the
generation of hydrogen peroxide with dichlorofluorescein
(DCF). However, daunorubicin (1 µmol/L) did not increase DCF
fluorescence, nor were the antioxidants
N-acetylcysteine or the combination of
-tocopherol and ascorbic acid able to prevent
apoptosis. In contrast, dexrazoxane (10 µmol/L), known
clinically to limit anthracycline cardiac toxicity, prevented
daunorubicin-induced myocyte apoptosis, but not necrosis
induced by higher anthracycline concentrations (10 µmol/L).
The antiapoptotic action of dexrazoxane was mimicked by the
superoxide-dismutase mimetic porphyrin
manganese(II/III)tetrakis(1-methyl-4-peridyl)porphyrin (50
µmol/L). The recognition that anthracycline-induced cardiac myocyte
apoptosis, perhaps mediated by superoxide anion generation,
occurs at concentrations well below those that result in myocyte
necrosis, may aid in the design of new therapeutic strategies to limit
the toxicity of these drugs.
Key Words: cardiotoxicity • dexrazoxane • superoxide anion • antioxidant
This article has been cited by other articles:
 |
|
 |
|
  J.-X. Wang, Q. Li, and P.-F. Li Apoptosis Repressor with Caspase Recruitment Domain Contributes to Chemotherapy Resistance by Abolishing Mitochondrial Fission Mediated by Dynamin-Related Protein-1 Cancer Res., January 15, 2009; 69(2): 492 - 500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Yano, D. Suzuki, M. Endoh, A. Tseng, J. P. Stabila, B. G. McGonnigal, T. C. Zhao, J. F. Padbury, and Y.-T. Tseng {beta}-Adrenergic Receptor Mediated Protection against Doxorubicin-Induced Apoptosis in Cardiomyocytes: The Impact of High Ambient Glucose Endocrinology, December 1, 2008; 149(12): 6449 - 6461. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-Z. Li, D.-Y. Lu, W.-Q. Tan, J.-X. Wang, and P.-F. Li p53 Initiates Apoptosis by Transcriptionally Targeting the Antiapoptotic Protein ARC Mol. Cell. Biol., January 15, 2008; 28(2): 564 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-H. Kim, G. Y. Oudit, and P. H. Backx Erythropoietin Protects against Doxorubicin-Induced Cardiomyopathy via a Phosphatidylinositol 3-Kinase-Dependent Pathway J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 160 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. d. de Tassigny, A. Berdeaux, R. Souktani, P. Henry, and B. Ghaleh The volume-sensitive chloride channel inhibitors prevent both contractile dysfunction and apoptosis induced by doxorubicin through PI3kinase, Akt and Erk 1/2 Eur J Heart Fail, January 1, 2008; 10(1): 39 - 46. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Fajardo and D. Bernstein Endocannabinoid Inhibition: A New Cardioprotective Strategy Against Doxorubicin Cardiotoxicity J. Am. Coll. Cardiol., August 7, 2007; 50(6): 537 - 539. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kuramochi, H. Takagi, and T. Morita Iloprost attenuates doxorubicin-induced cardiac injury in a murine model without compromising tumor suppression Eur. Heart J., November 1, 2006; 27(21): 2610 - 2611. [Full Text] [PDF]
|
|
|
|
 |
|
 T. L'Ecuyer, S. Sanjeev, R. Thomas, R. Novak, L. Das, W. Campbell, and R. V. Heide DNA damage is an early event in doxorubicin-induced cardiac myocyte death Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1273 - H1280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Chua, X. Liu, J. Gao, R. C. Hamdy, and B. H. L. Chua Multiple actions of pifithrin-{alpha} on doxorubicin-induced apoptosis in rat myoblastic H9c2 cells Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2606 - H2613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Hassan, S. Islam, M. M. Mu, H. Ito, N. Koide, I. Mori, T. Yoshida, and T. Yokochi Lipopolysaccharide Prevents Doxorubicin-Induced Apoptosis in RAW 264.7 Macrophage Cells by Inhibiting p53 Activation Mol. Cancer Res., July 1, 2005; 3(7): 373 - 379. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Peng, B. Chen, C. C. Lim, and D. B. Sawyer The Cardiotoxicology of Anthracycline Chemotherapeutics: TRANSLATING MOLECULAR MECHANISM INTO PREVENTATIVE MEDICINE Mol. Interv., June 1, 2005; 5(3): 163 - 171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. W. Fisher, F. Salloum, A. Das, H. Hyder, and R. C. Kukreja Phosphodiesterase-5 Inhibition With Sildenafil Attenuates Cardiomyocyte Apoptosis and Left Ventricular Dysfunction in a Chronic Model of Doxorubicin Cardiotoxicity Circulation, April 5, 2005; 111(13): 1601 - 1610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wang, E. A. Konorev, S. Kotamraju, J. Joseph, S. Kalivendi, and B. Kalyanaraman Doxorubicin Induces Apoptosis in Normal and Tumor Cells via Distinctly Different Mechanisms: INTERMEDIACY OF H2O2- AND p53-DEPENDENT PATHWAYS J. Biol. Chem., June 11, 2004; 279(24): 25535 - 25543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Minotti, P. Menna, E. Salvatorelli, G. Cairo, and L. Gianni Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity Pharmacol. Rev., June 1, 2004; 56(2): 185 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L'Ecuyer, Z. Allebban, R. Thomas, and R. Vander Heide Glutathione S-transferase overexpression protects against anthracycline-induced H9C2 cell death Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2057 - H2064. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tokudome, T. Horio, M. Fukunaga, H. Okumura, J. Hino, K. Mori, F. Yoshihara, S.-I. Suga, Y. Kawano, M. Kohno, et al. Ventricular Nonmyocytes Inhibit Doxorubicin-Induced Myocyte Apoptosis: Involvement of Endogenous Endothelin-1 as a Paracrine Factor Endocrinology, May 1, 2004; 145(5): 2458 - 2466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Lim, C. Zuppinger, X. Guo, G. M. Kuster, M. Helmes, H. M. Eppenberger, T. M. Suter, R. Liao, and D. B. Sawyer Anthracyclines Induce Calpain-dependent Titin Proteolysis and Necrosis in Cardiomyocytes J. Biol. Chem., February 27, 2004; 279(9): 8290 - 8299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. B. Hasinoff, P. E. Schroeder, and D. Patel The Metabolites of the Cardioprotective Drug Dexrazoxane Do Not Protect Myocytes from Doxorubicin-Induced Cytotoxicity Mol. Pharmacol., September 1, 2003; 64(3): 670 - 678. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Maejima, S. Adachi, H. Ito, K. Nobori, M. Tamamori-Adachi, and M. Isobe Nitric oxide inhibits ischemia/reperfusion-induced myocardial apoptosis by modulating cyclin A-associated kinase activity Cardiovasc Res, August 1, 2003; 59(2): 308 - 320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Yamanaka, T. Tatsumi, J. Shiraishi, A. Mano, N. Keira, S. Matoba, J. Asayama, S. Fushiki, H. Fliss, and M. Nakagawa Amlodipine inhibits doxorubicin-induced apoptosis in neonatal rat cardiac myocytes J. Am. Coll. Cardiol., March 5, 2003; 41(5): 870 - 878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Nitobe, S. Yamaguchi, M. Okuyama, N. Nozaki, M. Sata, T. Miyamoto, Y. Takeishi, I. Kubota, and H. Tomoike Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes Cardiovasc Res, January 1, 2003; 57(1): 119 - 128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Kwok and D. R. Richardson Unexpected Anthracycline-Mediated Alterations in Iron-Regulatory Protein-RNA-Binding Activity: The Iron and Copper Complexes of Anthracyclines Decrease RNA-Binding Activity Mol. Pharmacol., October 1, 2002; 62(4): 888 - 900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tokudome, T. Horio, F. Yoshihara, S.-i. Suga, Y. Kawano, M. Kohno, and K. Kangawa Adrenomedullin Inhibits Doxorubicin-Induced Cultured Rat Cardiac Myocyte Apoptosis via a cAMP-Dependent Mechanism Endocrinology, September 1, 2002; 143(9): 3515 - 3521. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zheng, C. Dimayuga, A. Hudaihed, and S. D. Katz Effect of Dexrazoxane on Homocysteine-Induced Endothelial Dysfunction in Normal Subjects Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): e15 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kotamraju, C. R. Chitambar, S. V. Kalivendi, J. Joseph, and B. Kalyanaraman Transferrin Receptor-dependent Iron Uptake Is Responsible for Doxorubicin-mediated Apoptosis in Endothelial Cells. ROLE OF OXIDANT-INDUCED IRON SIGNALING IN APOPTOSIS J. Biol. Chem., May 3, 2002; 277(19): 17179 - 17187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. V. Kalivendi, S. Kotamraju, H. Zhao, J. Joseph, and B. Kalyanaraman Doxorubicin-induced Apoptosis Is Associated with Increased Transcription of Endothelial Nitric-oxide Synthase. EFFECT OF ANTIAPOPTOTIC ANTIOXIDANTS AND CALCIUM J. Biol. Chem., December 7, 2001; 276(50): 47266 - 47276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Levade, N. Auge, R. J. Veldman, O. Cuvillier, A. Negre-Salvayre, and R. Salvayre Sphingolipid Mediators in Cardiovascular Cell Biology and Pathology Circ. Res., November 23, 2001; 89(11): 957 - 968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Qin, N. K. Rounds, W. Mao, K. Kawai, and C.-s. Liang Antioxidant vitamins prevent cardiomyocyte apoptosis produced by norepinephrine infusion in ferrets Cardiovasc Res, September 1, 2001; 51(4): 736 - 748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Negoro, H. Oh, E. Tone, K. Kunisada, Y. Fujio, K. Walsh, T. Kishimoto, and K. Yamauchi-Takihara Glycoprotein 130 Regulates Cardiac Myocyte Survival in Doxorubicin-Induced Apoptosis Through Phosphatidylinositol 3-Kinase/Akt Phosphorylation and Bcl-xL/Caspase-3 Interaction Circulation, January 30, 2001; 103(4): 555 - 561. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Konorev, H. Zhang, J. Joseph, M. C. Kennedy, and B. Kalyanaraman Bicarbonate exacerbates oxidative injury induced by antitumor antibiotic doxorubicin in cardiomyocytes Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2424 - H2430. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhu, Y. Zou, R. Aikawa, K. Harada, S. Kudoh, H. Uozumi, D. Hayashi, Y. Gu, T. Yamazaki, R. Nagai, et al. MAPK Superfamily Plays an Important Role in Daunomycin-Induced Apoptosis of Cardiac Myocytes Circulation, November 16, 1999; 100(20): 2100 - 2107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Siwik, J. D. Tzortzis, D. R. Pimental, D. L.-F. Chang, P. J. Pagano, K. Singh, D. B. Sawyer, and W. S. Colucci Inhibition of Copper-Zinc Superoxide Dismutase Induces Cell Growth, Hypertrophic Phenotype, and Apoptosis in Neonatal Rat Cardiac Myocytes In Vitro Circ. Res., July 23, 1999; 85(2): 147 - 153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kotamraju, E. A. Konorev, J. Joseph, and B. Kalyanaraman Doxorubicin-induced Apoptosis in Endothelial Cells and Cardiomyocytes Is Ameliorated by Nitrone Spin Traps and Ebselen. ROLE OF REACTIVE OXYGEN AND NITROGEN SPECIES J. Biol. Chem., October 20, 2000; 275(43): 33585 - 33592. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Pimentel, J. K. Amin, L. Xiao, T. Miller, J. Viereck, J. Oliver-Krasinski, R. Baliga, J. Wang, D. A. Siwik, K. Singh, et al. Reactive Oxygen Species Mediate Amplitude-Dependent Hypertrophic and Apoptotic Responses to Mechanical Stretch in Cardiac Myocytes Circ. Res., August 31, 2001; 89(5): 453 - 460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. Sawyer, C. Zuppinger, T. A. Miller, H. M. Eppenberger, and T. M. Suter Modulation of Anthracycline-Induced Myofibrillar Disarray in Rat Ventricular Myocytes by Neuregulin-1{beta} and Anti-erbB2: Potential Mechanism for Trastuzumab-Induced Cardiotoxicity Circulation, April 2, 2002; 105(13): 1551 - 1554. [Abstract] [Full Text] [PDF]
|
|