Roles of oxidative stress and Akt signaling in doxorubicin cardiotoxicity

Ichihara, Sahoko; Yamada, Yoshiji; Kawai, Yoshichika; Osawa, Toshihiko; Furuhashi, Koichi; Duan, Zhiwen; Ichihara, Gaku

doi:10.1016/j.bbrc.2007.05.027

Cited by 48 publications

(34 citation statements)

References 28 publications

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“…Histological observations excluded a widespread myocardial damage and a slight, but significant, activation of caspase-3 was detected at day 5 post-injection. Other authors have measured increases in the activity and level of cleaved form of caspase-3 in the heart of rodents following doxorubicin administration, with treatment protocols similar to our model, and the activation observed was also weak and time-dependent (Jang et al 2004;Ichihara et al 2007;Vitelli et al 2007). On the other hand, activation of calpains, an event usually associated to disturbances in calcium homeostasis and ATP levels, and leading to rapid cell death, was not detected in our experimental assays of rat heart homogenates.…”

Section: Discussionsupporting

confidence: 63%

“…This dose was selected after preliminary studies carried out in our laboratory with doses ranging from 10 to 40 mg of doxorubicin/kg body weight, aiming to set up a suitable protocol to detect the first, moderate but specific, signs of doxorubicin cardiotoxicity without a severe impairment of the animals. Equal or very similar doses are also used by other authors to investigate the effects of the drug in the heart and possible cardio protectors (Sadzuka et al 1997;Mihm et al 2002;Xiong et al 2006;Andreadou et al 2007;Ichihara et al 2007;Diotte et al 2009;Huelsenbeck et al 2011;Mokni et al 2012). …”

Section: Resultsmentioning

confidence: 99%

“…Previous works have shown that treatment of rat and mouse with doxorubicin doses about 15-20 mg/kg body weight induces cardiac dysfunction (Mihm et al 2002;Xiong et al 2006;Ichihara et al 2007;Diotte et al 2009) and lesion evidenced by morphological changes (SanchezQuintana et al 1994;Mihm et al 2002;Andreadou et al 2007) and increase of CK blood serum levels (Andreadou et al 2007;Diotte et al 2009), supporting the use of these treatments as experimental models of doxorubicin cardiomyopathy (Sanchez-Quintana et al 1994;Sadzuka et al 1997;Mihm et al 2002;Jang et al 2004;Xiong et al 2006;Andreadou et al 2007;Ichihara et al 2007;Diotte et al 2009;Huelsenbeck et al 2011;Mokni et al 2012). In good agreement with these results, we detected markers of myocardial lesion in the rats treated with doxorubicin in our model, specifically, cardiomyocyte degeneration and increase of CK in blood serum.…”

Section: Discussionmentioning

confidence: 99%

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The decrease of NAD(P)H:quinone oxidoreductase 1 activity and increase of ROS production by NADPH oxidases are early biomarkers in doxorubicin cardiotoxicity

Lagoa

Gañan²,

López‐Sánchez³

et al. 2014

Biomarkers

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Context. Doxorubicin cardiotoxicity displays a complex and multifactorial progression.Objective. Identify early biochemical mechanisms leading to a sustained imbalance of cellular bioenergetics.Methods. Measurements of the temporal evolution of selected biochemical markers after treatment of rats with doxorubicin (20 mg/kg body weight).Results. Doxorubicin treatment increased lipid oxidation, catalase activity and production of H2O2 by Nox-NADPH oxidases, and down-regulated NAD(P)H:quinone oxidoreductase-1 prior eliciting changes in reduced glutathione, protein carbonyls and protein nitrotyrosines. Alterations of mitochondrial and myofibrillar bioenergetics biomarkers were detected only after this oxidative imbalance was established.Conclusions. NAD(P)H:quinone oxidoreductase-1 activity and increase of hydrogen peroxide production by NADPH oxidases are early biomarkers in doxorubicin cardiotoxicity.

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Section: Discussionsupporting

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The decrease of NAD(P)H:quinone oxidoreductase 1 activity and increase of ROS production by NADPH oxidases are early biomarkers in doxorubicin cardiotoxicity

Lagoa

Gañan²,

López‐Sánchez³

et al. 2014

Biomarkers

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“…The antioxidant Trolox is readily available to cardiomyocytes under in vitro conditions and, thus, is able to efficiently scavenge free radicals. Furthermore, increased OS has been implicated in the process of apoptosis in the cardiomyocytes under multiple stress conditions (37)(38)(39)(40). In the current study, we report that Trolox induces a decrease in apoptotic proteins (PARP, caspase 3, Bax) and an increase in antiapoptotic protein (Bcl-xL).…”

Section: Discussionsupporting

confidence: 53%

Phosphorylation of AktSer473/Ask1Ser83 in Trolox-induced suppression of doxorubicin-induced changes in rat cardiomyocytes

Sharma¹,

Bagchi²,

Al‐Shudiefat³

et al. 2014

Curr Res Cardiol

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“…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)(7)(8). The use of cardioprotective drugs is an alternative approach to reduce the cardiotoxicity of DOX.…”

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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Roles of oxidative stress and Akt signaling in doxorubicin cardiotoxicity

Cited by 48 publications

References 28 publications

The decrease of NAD(P)H:quinone oxidoreductase 1 activity and increase of ROS production by NADPH oxidases are early biomarkers in doxorubicin cardiotoxicity

The decrease of NAD(P)H:quinone oxidoreductase 1 activity and increase of ROS production by NADPH oxidases are early biomarkers in doxorubicin cardiotoxicity

Phosphorylation of AktSer473/Ask1Ser83 in Trolox-induced suppression of doxorubicin-induced changes in rat cardiomyocytes

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

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