Lysosomal Alterations in Heart and Liver of Mice Treated with Doxorubicin

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 1985 Jan 1

PMID 4006046

Citations 6

Authors

N Gebbia

G Leto

M Gagliano

F M Tumminello

L Rausa

Affiliations

Soon will be listed here.

Abstract

This study was carried out to evaluate the influence of long-term treatment with doxorubicin (DXR) (4 mg/kg IV for 5 weeks) on heart and liver lysosomes of mice. We evaluated the variations in both total and "sedimentable" enzyme activity of cathepsin D, which is the major endopeptidase of myocites and probably involved in physiologic and pathologic degradation of actomyosin and mitochondria, and that of acid phosphatase, which is more prominent in interstitial cells. Our results show that marked changes occur in both total and sedimentable enzyme activity of cathepsin D in the heart of treated animals and to a lesser extent in the liver. In contrast, no modification of either total or sedimentable acid phosphatase was seen in either organ. The effects we observed are much more marked for cardiac cathepsin D; this is in good agreement with the cardiac specificity of DXR-induced cardiotoxicity with long-term administration and suggests that lysosomes could play a role in the pathogenesis of this phenomenon.

Citing Articles

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification.

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Hepatocyte Lysosomal Membrane Stabilization by Olive Leaves against Chemically Induced Hepatocellular Neoplasia in Rats.

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Premalignant variations in extracellular matrix composition in chemically induced hepatocellular carcinoma in rats.

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Reduced cardiotoxicity of doxorubicin given in the form of N-(2-hydroxypropyl)methacrylamide conjugates: and experimental study in the rat.

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References

Doroshow J . Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res. 1983; 43(2):460-72. View

DE DUVE C, de Barsy T, Poole B, Trouet A, Tulkens P, Van Hoof F . Commentary. Lysosomotropic agents. Biochem Pharmacol. 1974; 23(18):2495-531. DOI: 10.1016/0006-2952(74)90174-9. View

Allan R, Welman E . Proteolysis of isolated mitochondria by myocardial lysosomal enzymes. Biochem J. 1980; 190(1):139-44. PMC: 1162072. DOI: 10.1042/bj1900139. View

Mettler F, Young D, Ward J . Adriamycin-induced cardiotoxicity (cardiomyopathy and congestive heart failure) in rats. Cancer Res. 1977; 37(8 Pt 1):2705-13. View

Ruysschaert J, Hildebrand J . Affinity of adriamycin to phospholipids. A possible explanation for cardiac mitochondrial lesions. Biochem Biophys Res Commun. 1976; 71(2):658-63. DOI: 10.1016/0006-291x(76)90838-x. View

Dusonchet L, Crosta L, Bellini O, Flandina C, Palmeri S, Valvo F . The influence of multiple treatment with doxorubicin or 4'-deoxy-doxorubicin on the DNA synthesis and morphology of mouse heart. Int J Tissue React. 1984; 6(1):81-9. View

Thayer W . Adriamycin stimulated superoxide formation in submitochondrial particles. Chem Biol Interact. 1977; 19(3):265-78. DOI: 10.1016/0009-2797(77)90050-3. View

Noel G, Peterson C, Trouet A, Tulkens P . Uptake and subcellular localization of daunorubicin and adriamycin in cultured fibroblasts. Eur J Cancer (1965). 1978; 14(4):363-8. DOI: 10.1016/0014-2964(78)90206-2. View

Bristow M, Sageman W, Scott R, Billingham M, Bowden R, Kernoff R . Acute and chronic cardiovascular effects of doxorubicin in the dog: the cardiovascular pharmacology of drug-induced histamine release. J Cardiovasc Pharmacol. 1980; 2(5):487-515. DOI: 10.1097/00005344-198009000-00002. View

10.

Bachur N, Gordon S, Gee M . A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res. 1978; 38(6):1745-50. View

11.

Schwartz W, BIRD J . Degradation of myofibrillar proteins by cathepsins B and D. Biochem J. 1977; 167(3):811-20. PMC: 1183729. DOI: 10.1042/bj1670811. View

12.

Hines J, Ogunro E, Ferguson A, Lesch M . Cathepsin D catalyzed degradation of cardiac mitochondria. A study of enzyme inactivation and ultrastructure. J Mol Cell Cardiol. 1982; 14(2):91-7. DOI: 10.1016/0022-2828(82)90197-3. View

13.

Ogunro E, Lanman R, Spencer J, Ferguson A, Lesch M . Degradation of canine cardiac myosin and actin by cathepsin D isolated from homologous tissue. Cardiovasc Res. 1979; 13(11):621-9. DOI: 10.1093/cvr/13.11.621. View

14.

Barrett A, DINGLE J . The inhibition of tissue acid proteinases by pepstatin. Biochem J. 1972; 127(2):439-41. PMC: 1178605. DOI: 10.1042/bj1270439. View

15.

Jaenke R . An anthracycline antibiotic-induced cardiomyopathy in rabbits. Lab Invest. 1974; 30(3):292-304. View

16.

Solcia E, Ballerini L, Bellini O, Magrini U, BERTAZZOLI C, Tosana G . Cardiomyopathy of doxorubicin in experimental animals, Factors affecting the severity, distribution and evolution of myocardial lesions. Tumori. 1981; 67(5):461-72. DOI: 10.1177/030089168106700512. View

17.

Wildenthal K . Lysosomal alterations in ischemic myocardium: result or cause of myocellular damage?. J Mol Cell Cardiol. 1978; 10(7):595-603. DOI: 10.1016/s0022-2828(78)80001-7. View

18.

Murphree S, Cunningham L, Hwang K, Sartorelli A . Effects of adriamycin on surface properties of sarcoma 180 ascites cells. Biochem Pharmacol. 1976; 25(10):1227-31. DOI: 10.1016/0006-2952(76)90374-9. View

19.

LOWRY O, ROSEBROUGH N, FARR A, RANDALL R . Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1):265-75. View

20.

Morgan H, Rannels D, Kao R . Factors controlling protein turnover in heart muscle. Circ Res. 1974; 35 Suppl 3:22-31. View