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1.
Cancer Sci ; 107(11): 1610-1621, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27560771

ABSTRACT

Chemotherapy, radiotherapy, and endocrinotherapy are documented to induce autophagy among breast cancer cells, but the role of autophagy in this disease has been attributed as cytoprotective as well as tumor-suppressing. Thus we studied MDA-MB-231 and SK-BR-3 breast cancer cell lines treated with epirubicin (EPI) to assess autophagy and apoptosis. We found out that EPI induced apoptosis and autophagy in both cell lines. The lysosomal inhibitor bafilomycin A1 inhibited cellular autophagy and enhanced EPI-triggered apoptosis, perhaps due to inhibition of autolysosome formation, which then inhibited autophagic effects of engulfing and clearing damaged mitochondria. This inhibition increased mitochondrial cytochrome C release which augmented epirubicin-induced caspase-dependent apoptosis and cytotoxicity. In addition, the lysosomal neutralizing agent ammonia chloride (AC), and Atg7 knockdown by siRNA, could inhibit epirubicin-triggered autophagy, enhance cytotoxicity, and increase caspase-9- and caspase-3-dependent apoptosis. Thus, autophagy plays a prosurvival role in EPI-treated MDA-MB-231 and SK-BR-3 cells, and autophagy inhibition can potentially reverse this effect and increase the cytotoxicity of EPI.


Subject(s)
Autophagy/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Epirubicin/pharmacology , Ammonium Chloride/pharmacology , Apoptosis/drug effects , Autophagosomes/drug effects , Breast Neoplasms/enzymology , Caspase 3/metabolism , Caspase 9/metabolism , Cell Line, Tumor , Cytochromes c/metabolism , Epirubicin/antagonists & inhibitors , Humans , In Situ Nick-End Labeling , Lysosomes/drug effects , Lysosomes/metabolism , Macrolides/pharmacology , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/pathology , Neoplastic Stem Cells
2.
J Pharmacol Sci ; 130(1): 33-7, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26809377

ABSTRACT

We investigated the involvement of intracellular cAMP in endothelial cell injury induced by epirubicin. Epirubicin-induced decrease in cell viability and increase in caspase-3/7 activity were reversed by a cAMP analog dibutyryl cAMP (DBcAMP) or an activator of adenylate cyclase forskolin concomitant with a phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Moreover, epirubicin-induced elevation of lipid peroxide levels was attenuated by DBcAMP. Interestingly, the exposure of epirubicin decreased intracellular cAMP levels before the onset of epirubicin-induced production of lipid peroxidation. These results suggest that intracellular cAMP plays an important role in epirubicin-induced endothelial cell injury.


Subject(s)
Apoptosis/drug effects , Cyclic AMP/physiology , Endothelial Cells/drug effects , Endothelial Cells/pathology , Epirubicin/adverse effects , Epirubicin/antagonists & inhibitors , 1-Methyl-3-isobutylxanthine/pharmacology , Albuterol, Ipratropium Drug Combination , Animals , Bucladesine/pharmacology , Caspase 3/metabolism , Caspase 7/metabolism , Cell Survival/drug effects , Cells, Cultured , Colforsin/pharmacology , Cyclic AMP/metabolism , Endothelial Cells/metabolism , Lipid Peroxidation/drug effects , Lipid Peroxides/metabolism , Swine
3.
Nutr Cancer ; 51(2): 178-83, 2005.
Article in English | MEDLINE | ID: mdl-15860440

ABSTRACT

Polyunsaturated fatty acids (PUFAs) have been reported to enhance the efficacy of chemotherapeutic agents that produce reactive oxygen species such as anthracyclines. We previously reported in a human breast cancer cell line that the increased cytotoxic activity of anthracyclines by several PUFAs was abolished by antioxidants and enhanced by pro-oxidants, suggesting that lipid peroxidation was involved in this effect. To determine the relevance of this observation in vivo, we examined the effect of the oxidative status of the diet on the activity of epirubicin against N-methylnitrosourea-induced mammary tumors in Sprague-Dawley rats. Three groups of rats were fed a basal diet enriched with dietary n-3 PUFA (sardine oil, 15%) alone (control group), with addition of an antioxidant (alpha-tocopherol, 100 UI/kg diet), or with addition of an oxidant system (dehydroascorbate/naphthoquinone). When the first mammary tumor reached 1 cm2, epirubicin was administrated weekly for 3 wk, and subsequent change in tumor size was documented over time. Two weeks after the end of epirubicin injections, tumor size was increased by 34% in the control group. In the pro-oxidant group, tumor size was decreased by 50%. In contrast, tumor size was increased by 188% in the antioxidant group. Thus, addition of pro-oxidants in a fish oil-enriched diet increased the sensitization of mammary tumors to chemotherapy, whereas addition of alpha-tocopherol suppressed tumor response in vivo, indicating that interaction between components of the diet has to be carefully controlled during chemotherapy.


Subject(s)
Anthracyclines/antagonists & inhibitors , Anthracyclines/pharmacology , Antioxidants/pharmacology , Diet/adverse effects , Drug Resistance, Neoplasm/drug effects , Fish Oils/administration & dosage , Mammary Neoplasms, Experimental/drug therapy , alpha-Tocopherol/pharmacology , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Antibiotics, Antineoplastic/antagonists & inhibitors , Antibiotics, Antineoplastic/pharmacology , Carcinogens , Disease Models, Animal , Drug Antagonism , Epirubicin/antagonists & inhibitors , Epirubicin/pharmacology , Fatty Acids, Unsaturated/pharmacology , Female , Malondialdehyde/metabolism , Mammary Neoplasms, Experimental/chemically induced , Methylnitrosourea , Oxidants/administration & dosage , Rats , Rats, Sprague-Dawley , Time Factors
4.
Toxicol Pathol ; 24(4): 398-402, 1996.
Article in English | MEDLINE | ID: mdl-8864181

ABSTRACT

The long-lasting protective effect of dexrazoxane (ADR-529) against doxorubicin- and epirubicin-induced cardiotoxicity was evaluated in the multiple-dose 35-wk rat model. Groups of 36 male Sprague-Dawley rats were given ADR-529 30 min before administration of cardiotoxic doses of doxorubicin (1 mg/kg/wk) or epirubicin (1.13 mg/kg/wk). The compounds were intravenously injected once weekly for 7 consecutive wk at ADR-529; anthracycline ratios ranging from 5:1 to 20:1. These ratios covered the entire chemotherapeutic range in humans and allowed studying the chronic progressive cardiomyopathy in our rat model. Animals were observed for up to 35 wk to follow the time course of the well-characterized cardiomyopathy, which was evaluated through the well-established qualitative/quantitative morphological grading. It was clearly demonstrated in this rat model that ADR-529, at the ratios administered, provided ample cardioprotection for a duration of 35 wk, which corresponds to 25 yr of equivalent human time.


Subject(s)
Antibiotics, Antineoplastic/toxicity , Cardiomyopathies/chemically induced , Cardiovascular Agents/pharmacology , Razoxane/pharmacology , Animals , Antibiotics, Antineoplastic/antagonists & inhibitors , Cardiomyopathies/pathology , Cardiomyopathies/prevention & control , Doxorubicin/antagonists & inhibitors , Doxorubicin/toxicity , Epirubicin/antagonists & inhibitors , Epirubicin/toxicity , Injections, Intravenous , Male , Monocytes/drug effects , Monocytes/physiology , Monocytes/ultrastructure , Myocardium/pathology , Myocardium/ultrastructure , Rats , Rats, Sprague-Dawley
5.
Eur J Cancer Clin Oncol ; 25(2): 361-8, 1989 Feb.
Article in English | MEDLINE | ID: mdl-2467809

ABSTRACT

Epirubicin induces an important noncytotoxic release of histamine from rat peritoneal cells in vitro. This exocytotic response is inhibited by sodium cromoglycate, similarly to that elicited by the classic mast cell secretagogue, compound 48/80. Mast cells obtained from the peritoneal cavities of rats treated with epirubicin in vivo were extensively degranulated; in contrast, samples obtained from rats pretreated with sodium cromoglycate showed normal appearing mast cells. When injected i.p., immediately before the antineoplastic agent, cromolyn significantly improved the survival time and the microscopic appearance of myocardial tissues of epirubicin-treated mice. The results indicate that histamine release could play an important role in the pathogenesis of anthracycline-induced cardiotoxicity.


Subject(s)
Cardiomyopathies/prevention & control , Cromolyn Sodium/therapeutic use , Epirubicin/adverse effects , Animals , Cardiomyopathies/chemically induced , Cytoplasmic Granules/drug effects , Epirubicin/antagonists & inhibitors , Histamine Release/drug effects , Male , Mast Cells/metabolism , Mast Cells/ultrastructure , Mice , Mice, Inbred Strains , Microscopy, Electron , Rats , Rats, Inbred Strains
6.
Cancer Chemother Pharmacol ; 24(2): 105-8, 1989.
Article in English | MEDLINE | ID: mdl-2543512

ABSTRACT

Rat-liver microsomes and NADPH could reduce Adriamycin, epirubicin and daunorubicin to their free radical forms, which enhanced peroxidation of microsomal lipids less than 2-fold in air but 3- to 5-fold at a pO2 of 4 mmHg. Mitoxantrone was not reduced by microsomes and had no effect on microsomal peroxidation. Daunorubicin caused more lipid peroxidation than similar concentrations of either Adriamycin or epirubicin, which were equally efficient. In each case peroxidation was iron-dependent and could be catalysed by ferritin. The antioxidants beta-carotene and alpha-tocopherol inhibited lipid peroxidation at low or high pO2. The dose-for-dose difference in the cardiotoxicity of epirubicin compared with Adriamycin is not explained by its effect on microsomal lipid peroxidation. However, the lower incidence of cardiotoxicity with mitoxantrone may be a consequence of its inability to form free radical species and promote lipid peroxidation.


Subject(s)
Daunorubicin/pharmacology , Doxorubicin/pharmacology , Epirubicin/pharmacology , Lipid Peroxidation/drug effects , Microsomes, Liver/drug effects , Mitoxantrone/pharmacology , Animals , Carotenoids/pharmacology , Catalysis , Cytochrome c Group/metabolism , Daunorubicin/antagonists & inhibitors , Doxorubicin/antagonists & inhibitors , Epirubicin/antagonists & inhibitors , Ferritins/pharmacology , Iron/pharmacology , Microsomes, Liver/metabolism , Oxidation-Reduction , Oxygen/pharmacology , Partial Pressure , Rats , Rats, Inbred Strains , Vitamin E/pharmacology , beta Carotene
7.
Anticancer Res ; 8(6): 1229-32, 1988.
Article in English | MEDLINE | ID: mdl-3218957

ABSTRACT

In attempts to alleviate or prevent anthracycline toxicity, we have recently reported that amrinone and sulmazole markedly reduce the negative inotropic effect of adriamycin and 4-epiadriamycin in isolated spontaneously beating guinea pig atria in normodynamic or hypodynamic conditions. Amrinone and sulmazole are non catecholamine, non glycoside agents with inotropic properties. The present study reports the effects of adriamycin and 4-epiadriamycin (100 micrograms/ml) on electrically driven isolated guinea pig left atrium in normodynamic or hypodynamic conditions. Exposure for 60' to the two drugs caused a depression of contractile force and of maximal rate of contractile force (df/dt). The cardiac depressant effect of adriamycin as shown previously on spontaneously beating atria does not differ from that of 4-epiadriamycin. The negative effects of the two antitumor drugs are antagonized by amrinone (200 micrograms/ml) and sulmazole (100 micrograms/ml).


Subject(s)
Amrinone/pharmacology , Cardiotonic Agents/pharmacology , Doxorubicin/toxicity , Epirubicin/toxicity , Imidazoles/pharmacology , Myocardial Contraction/drug effects , Animals , Atrial Function , Doxorubicin/antagonists & inhibitors , Electric Stimulation , Epirubicin/antagonists & inhibitors , Guinea Pigs , Heart Atria/drug effects , In Vitro Techniques
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