Doxorubicin in experimental and clinical heart failure

Christiansen, Stefan; Autschbach, Rüdiger

doi:10.1016/j.ejcts.2006.06.024

Cited by 65 publications

(43 citation statements)

References 61 publications

(104 reference statements)

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“…Caspase-3 activation is a key step in apoptosis. Accordingly, inhibition of doxorubicin-induced cardiomyocyte apoptosis by modulation of the factors that control apoptosis may provide new opportunities for the prevention and treatment of doxorubicin-induced cardiomyopathy (Christiansen and Autschbach, 2006;Narula et al, 1999;Takemura and Fujiwara, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that the development of doxorubicin cardiomyopathy involves apoptosis of cardiomyocytes (L'Ecuyer et al, 2006;Takemura and Fujiwara, 2007). Since cardiomyocyte apoptosis contributes to the development of myocardial dysfunction in heart failure, inhibition of doxorubicin-induced cardiomyocyte apoptosis may provide new opportunities for the prevention and treatment of doxorubicin-induced heart failure (Christiansen and Autschbach, 2006). …”

Section: Introductionmentioning

confidence: 99%

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Protective effects of naringenin-7-O-glucoside on doxorubicin-induced apoptosis in H9C2 cells

Han

Ren

Fan

et al. 2008

European Journal of Pharmacology

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Doxorubicin, a widely used chemotherapeutic agent, can give rise to severe cardiotoxicity by inducing cardiomyocyte apoptosis. Dracocephalum rupestre Hance, a Chinese traditional herb, has therapeutic potential for cardiovascular diseases. Naringenin-7-O-glucoside is the main active constituent of D. rupestre and there is increasing interest in its therapeutic applications. The aim of this study was to evaluate the effects of naringenin-7-O-glucoside on cardiomyocyte apoptosis induced by doxorubicin. Cell viability was detected by MTT assay. Naringenin-7-Oglucoside (10, 20, and 40 μM) significantly enhanced cardiomyocyte proliferation relative to that of doxorubicin. Furthermore, naringenin-7-Oglucoside increased the protein levels of heme oxygenase-1 (HO-1) and Bcl-2 in cardiomyocytes (as detected by Western blotting) and suppressed the mRNA expression of caspase-3 and caspase-9 (as detected by RT-PCR). These results suggest that naringenin-7-O-glucoside has protective effects against doxorubicin-induced apoptosis, effects which could underlie the use of naringenin-7-O-glucoside therapeutic agent for treating or preventing cardiomyopathy associated with doxorubicin.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protective effects of naringenin-7-O-glucoside on doxorubicin-induced apoptosis in H9C2 cells

Han

Ren

Fan

et al. 2008

European Journal of Pharmacology

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“…However, the clinical use of this drug is limited because of cardiotoxicity, which might proceed to irreversible heart failure (Swain et al, 2003;Christiansen and Autschbach, 2006;Outomuro et al, 2007;Carvalho et al, 2009). Although several mechanisms have been proposed to describe the mechanisms by which DOX induces cardiotoxicity, these mechanisms are still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Chronic Doxorubicin Cardiotoxicity Modulates Cardiac Cytochrome P450-Mediated Arachidonic Acid Metabolism in Rats

et al. 2012

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ABSTRACT:Doxorubicin [(DOX) Adriamycin] is an effective anticancer agent whose major limiting side effect is cardiotoxicity. This cardiotoxicity is predicted only by the cumulative dose of DOX where the clinical situation involves chronic drug administration. Therefore, we investigate the effect of chronic DOX cardiotoxicity on expression of the cardiac cytochrome P450 (P450) enzymes and arachidonic acid (AA) metabolism in male Sprague-Dawley (SD) rats. The chronic toxicity was induced by multiple intraperitoneal injections for a cumulative dose of 15 mg/kg divided into six injections within 2 weeks. After 14 days of the last injection, the heart, liver, and kidney were harvested, and the expression of different genes was determined by real-time polymerase chain reaction. In addition, microsomal protein from the heart was prepared and incubated with AA. Thereafter, different AA metabolites were analyzed by liquid chromatography-electrospray ionization-mass spectrometry. The chronic DOX cardiotoxicity significantly induced gene expression of hypertrophic markers, apoptotic markers, CYP2E1, CYP4A3, CYP4F1, CYP4F5, and soluble epoxide hydrolase (sEH) enzyme, which was accompanied by an increase in the activity of P450 -hydroxylases and sEH. In addition, both the sEH inhibitor, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid, and the -hydroxylase inhibitor, N-hydroxy-N-(4-butyl-2-methylphenyl)-formamidine (HET0016), significantly prevented the DOX-mediated induction of the hypertrophic markers in the cardiacderived H9c2 cells, which further confirms the role of these enzymes in DOX cardiotoxicity. Furthermore, gene expression of P450 and sEH was altered in an organ-specific manner. As a result, the chronic DOX administration leads to an imbalance between P450-mediated cardiotoxic and cardioprotective pathways. Therefore, P450 -hydroxylases and sEH might be considered as novel targets to prevent and/or treat DOX cardiotoxicity.

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“…DOX is a potent chemotherapeutic agent that is used in the treatment of solid tumors and malignant hematological diseases (2). DOX exerts its antitumor activity by inserting into DNA, leading to double-stranded DNA breaks (DSB), and intercepting DNA topoisomerase II activity (3,4).…”

Section: Introductionmentioning

confidence: 99%

Berberine sensitizes mutliple human cancer cells to the anticancer effects of doxorubicin in vitro

et al. 2012

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Abstract. The clinical use of doxorubicin (DOX), a potent antineoplastic agent, is limited by its serious side-effects, which include acute and chronic cumulative dose-related cardiotoxicity. Berberine (BER), a botanical alkaloid, has been reported to possess cardioprotective and antitumor effects. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-tetrazolium bromide (MTT) assay was used to detect the cell viability of A549, HeLa and HepG2 cells after each cell line was treated with DOX, BER or a combination of DOX and BER for 24 h. Apoptosis was evaluated by acridine orange staining. The results showed that BER and DOX exhibited dose-dependent inhibitory effects on A549 and HeLa cells which were likely mediated by inducing apoptosis. The same result was found in the combination group. Isobologram illustration and combination index (CI) analyses revealed that the combination of DOX and BER generates synergistic effects in A549 (CI=0.61) and HeLa (CI= 0.73) cells. These findings indicate that BER sensitizes cells to the anticancer effects of DOX. IntroductionDoxorubicin (DOX), an anthracycline antibiotic and antineoplastic agent, was first isolated from Streptomyces peucetius (1). DOX is a potent chemotherapeutic agent that is used in the treatment of solid tumors and malignant hematological diseases (2). DOX exerts its antitumor activity by inserting into DNA, leading to double-stranded DNA breaks (DSB), and intercepting DNA topoisomerase II activity (3,4). However, the clinical use of DOX has been largely restricted due to its cardiotoxicity, which may lead to the development of cardiomyopathy and ultimately congestive heart failure (5). The molecular mechanisms underlying DOX-induced cardiotoxicity include the formation of free radicals, activation of transcription factor NF-κB, increased lipid peroxidation and Ca 2+ overloading (6-8). The use of cardioprotective drugs is an alternative approach to reduce the cardiotoxicity of DOX. Pharmacological and clinical attempts to reduce the cardiotoxicity of DOX have had little success thus far. Consequently, it is important to develop a therapy to reduce DOX-induced cardiotoxicity and increase the antitumor effect of DOX.Berberine (BER), a botanical alkaloid, is purified from the roots and bark of the Berberis species (9). BER reportedly possesses multiple biological and pharmacological properties, including anti-diarrheal, anti-fungal, anti-diabetic (10-12), hepatoprotective and cardioprotective effects. The possible mechanism of the hepatoprotective effect is that BER inhibits the activity of CYP 2E1 and CYP 1A2, reduces the production of nitric oxide and lowers the AST and ALT levels in serum (13,14). For the cardioprotective property, BER is known to modulate Cdk9 and cyclin T1 protein expression. BER possesses muscarinic agonist-like properties which may contribute to a reduction in myocardial damage (15-17). BER also suppresses tumor growth through the induction of apoptosis and cell cycle arrest in cancer cells (18)(19)(20)(21). Notably, it has been reported tha...

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Doxorubicin in experimental and clinical heart failure

Cited by 65 publications

References 61 publications

Protective effects of naringenin-7-O-glucoside on doxorubicin-induced apoptosis in H9C2 cells

Protective effects of naringenin-7-O-glucoside on doxorubicin-induced apoptosis in H9C2 cells

Chronic Doxorubicin Cardiotoxicity Modulates Cardiac Cytochrome P450-Mediated Arachidonic Acid Metabolism in Rats

Berberine sensitizes mutliple human cancer cells to the anticancer effects of doxorubicin in vitro

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