Doxorubicin Cardiomyopathy is Associated with a Decrease in Calcium Release Channel of the Sarcoplasmic Reticulum in a Chronic Rabbit Model

Overview

Journal J Clin Invest

Specialty General Medicine

Date 1993 Apr 1

PMID 8386192

Citations 22

Authors

D A Dodd

J B Atkinson

R D Olson

S Buck

B J Cusack

S Fleischer

R J Boucek Jr

Affiliations

Soon will be listed here.

Abstract

Doxorubicin is a highly effective cancer chemotherapeutic agent that produces a dose-dependent cardiomyopathy that limits its clinical usefulness. Clinical and animal studies of morphological changes during the early stages of doxorubicin-induced cardiomyopathy have suggested that the sarcoplasmic reticulum, the intracellular membrane system responsible for myoplasmic calcium regulation in adult mammalian heart, may be the early target of doxorubicin. To detect changes in the calcium pump protein or the calcium release channel (ryanodine receptor) of the sarcoplasmic reticulum during chronic doxorubicin treatment, rabbits were treated with intravenous doxorubicin (1 mg/kg) twice weekly for 12 to 18 doses. Pair-fed controls received intravenous normal saline. The severity of cardiomyopathy was scored by light and electron microscopy of left ventricular papillary muscles. Developed tension was measured in isolated atrial strips. In subcellular fractions from heart, [3H]ryanodine binding was decreased in doxorubicin-treated rabbits (0.33 +/- 0.03 pmol/mg) compared with control rabbits (0.66 +/- 0.02 pmol/mg; P < 0.0001). The magnitude of the decrease in [3H]ryanodine binding correlated with both the severity of the cardiomyopathy graded by pathology score (light and electron microscopy) and the decrease in developed tension in isolated atrial strips. Bmax for [3H]ryanodine binding and the amount of immunoreactive ryanodine receptor by Western blot analysis using sequence-specific antibody were both decreased, consistent with a decrease in the amount of calcium release channel of sarcoplasmic reticulum in doxorubicin-treated rabbits. In contrast, there was no decrease in the amount or the activity of the calcium pump protein of the sarcoplasmic reticulum in doxorubicin-treated rabbits. Doxorubicin treatment did not decrease [3H]ryanodine binding or the amount of immunoreactive calcium release channel of sarcoplasmic reticulum in skeletal muscle. Since the sarcoplasmic reticulum regulates muscle contraction by the cyclic uptake and release of a large internal calcium pool, altered function of the calcium release channel could lead to the abnormalities of contraction and relaxation observed in the doxorubicin cardiomyopathy.

Citing Articles

Serum Biomarkers for Chemotherapy Cardiotoxicity Risk Detection of Breast Cancer Patients.

Hasan D, Ismail Y, Al Tibi A, Al-Zeidaneen S, Odeh M, Burghel G Asian Pac J Cancer Prev. 2021; 22(10):3355-3363.

PMID: 34711013 PMC: 8858245. DOI: 10.31557/APJCP.2021.22.10.3355.

Noncoding RNAs in doxorubicin-induced cardiotoxicity and their potential as biomarkers and therapeutic targets.

Fa H, Chang W, Zhang X, Xiao D, Wang J Acta Pharmacol Sin. 2020; 42(4):499-507.

PMID: 32694762 PMC: 8114921. DOI: 10.1038/s41401-020-0471-x.

Modulation of Nrf2 by quercetin in doxorubicin-treated rats.

Sharma A, Parikh M, Shah H, Gandhi T Heliyon. 2020; 6(4):e03803.

PMID: 32337383 PMC: 7177035. DOI: 10.1016/j.heliyon.2020.e03803.

Carbonyl Reductase 1 Plays a Significant Role in Converting Doxorubicin to Cardiotoxic Doxorubicinol in Mouse Liver, but the Majority of the Doxorubicinol-Forming Activity Remains Unidentified.

Breysse D, Boone R, Long C, Merrill M, Schaupp C, White C Drug Metab Dispos. 2020; 48(3):187-197.

PMID: 31955137 PMC: 7011114. DOI: 10.1124/dmd.119.089326.

Transcriptomic profiling reveals p53 as a key regulator of doxorubicin-induced cardiotoxicity.

McSweeney K, Bozza W, Alterovitz W, Zhang B Cell Death Discov. 2019; 5:102.

PMID: 31231550 PMC: 6561911. DOI: 10.1038/s41420-019-0182-6.

References

Julicher R, Sterrenberg L, Bast A, Riksen R, Koomen J, Noordhoek J . The role of lipid peroxidation in acute doxorubicin-induced cardiotoxicity as studied in rat isolated heart. J Pharm Pharmacol. 1986; 38(4):277-82. DOI: 10.1111/j.2042-7158.1986.tb04566.x. View

Chadwick C, Saito A, Fleischer S . Isolation and characterization of the inositol trisphosphate receptor from smooth muscle. Proc Natl Acad Sci U S A. 1990; 87(6):2132-6. PMC: 53640. DOI: 10.1073/pnas.87.6.2132. View

Zorzato F, Margreth A, Volpe P . Direct photoaffinity labeling of junctional sarcoplasmic reticulum with [14C]doxorubicin. J Biol Chem. 1986; 261(28):13252-7. View

Trimm J, Salama G, Abramson J . Sulfhydryl oxidation induces rapid calcium release from sarcoplasmic reticulum vesicles. J Biol Chem. 1986; 261(34):16092-8. View

Palade P . Drug-induced Ca2+ release from isolated sarcoplasmic reticulum. II. Releases involving a Ca2+-induced Ca2+ release channel. J Biol Chem. 1987; 262(13):6142-8. View

Schwartz R, McKenzie W, Alexander J, Sager P, Dsouza A, Manatunga A . Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography. Am J Med. 1987; 82(6):1109-18. DOI: 10.1016/0002-9343(87)90212-9. View

Boucek Jr R, Olson R, Brenner D, Ogunbunmi E, Inui M, Fleischer S . The major metabolite of doxorubicin is a potent inhibitor of membrane-associated ion pumps. A correlative study of cardiac muscle with isolated membrane fractions. J Biol Chem. 1987; 262(33):15851-6. View

Singal P, Deally C, Weinberg L . Subcellular effects of adriamycin in the heart: a concise review. J Mol Cell Cardiol. 1987; 19(8):817-28. DOI: 10.1016/s0022-2828(87)80392-9. View

Salviati G, Volpe P . Ca2+ release from sarcoplasmic reticulum of skinned fast- and slow-twitch muscle fibers. Am J Physiol. 1988; 254(3 Pt 1):C459-65. DOI: 10.1152/ajpcell.1988.254.3.C459. View

10.

Abramson J, Buck E, Salama G, Casida J, Pessah I . Mechanism of anthraquinone-induced calcium release from skeletal muscle sarcoplasmic reticulum. J Biol Chem. 1988; 263(35):18750-8. View

11.

Chu A, Dixon M, Saito A, Seiler S, Fleischer S . Isolation of sarcoplasmic reticulum fractions referable to longitudinal tubules and junctional terminal cisternae from rabbit skeletal muscle. Methods Enzymol. 1988; 157:36-46. DOI: 10.1016/0076-6879(88)57066-0. View

12.

Chamberlain B, Fleischer S . Isolation of canine cardiac sarcoplasmic reticulum. Methods Enzymol. 1988; 157:91-9. DOI: 10.1016/0076-6879(88)57071-4. View

13.

McGrew S, Wolleben C, Siegl P, Inui M, Fleischer S . Positive cooperativity of ryanodine binding to the calcium release channel of sarcoplasmic reticulum from heart and skeletal muscle. Biochemistry. 1989; 28(4):1686-91. DOI: 10.1021/bi00430a039. View

14.

Nagasaki K, Fleischer S . Modulation of the calcium release channel of sarcoplasmic reticulum by adriamycin and other drugs. Cell Calcium. 1989; 10(1):63-70. DOI: 10.1016/0143-4160(89)90045-6. View

15.

Fleischer S, Inui M . Biochemistry and biophysics of excitation-contraction coupling. Annu Rev Biophys Biophys Chem. 1989; 18:333-64. DOI: 10.1146/annurev.bb.18.060189.002001. View

16.

Lefrak E, Pitha J, ROSENHEIM S, Gottlieb J . A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer. 1973; 32(2):302-14. DOI: 10.1002/1097-0142(197308)32:2<302::aid-cncr2820320205>3.0.co;2-2. View

17.

Bachur N, Hildebrand R, Jaenke R . Adriamycin and daunorubicin disposition in the rabbit. J Pharmacol Exp Ther. 1974; 191(2):331-40. View

18.

Olson H, Young D, Prieur D, LeRoy A, REAGAN R . Electrolyte and morphologic alterations of myocardium in adriamycin-treated rabbits. Am J Pathol. 1974; 77(3):439-54. PMC: 1910923. View

19.

Jaenke R . Delayed and progressive myocardial lesions after adriamycin administration in the rabbit. Cancer Res. 1976; 36(8):2958-66. View

20.

Myers C, McGuire W, Liss R, Ifrim I, Grotzinger K, Young R . Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science. 1977; 197(4299):165-7. DOI: 10.1126/science.877547. View