Early Administration of Carvedilol Protected against Doxorubicin-Induced Cardiomyopathy

Chen, Yung‐Lung; Chung, Sheng-Ying; Chai, Han‐Tan; Chen, Chih‐Hung; Liu, Chu-Feng; Huang, Tung‐Liang; Zhen, Yen-Yi; Sung, Pei‐Hsun; Sun, Cheuk‐Kwan; Chua, Sarah; Lu, Hung-I; Lee, Fan-Yen; Sheu, Jiunn‐Jye; Yip, Hon‐Kan

doi:10.1124/jpet.115.225375

Cited by 38 publications

(48 citation statements)

References 37 publications

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“…LVIDd was markedly reduced after DOX in all mice (Table 2), consistent with cardiac atrophy, as seen in mice and humans with anthracycline cardiomyopathy [25,26,27]. Reduced heart weight at study end supported the conclusion of cardiac atrophy (below).…”

Section: Resultssupporting

confidence: 69%

An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice

et al. 2017

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Alpha-1 adrenergic receptors mediate adaptive effects in the heart and cardiac myocytes, and a myocyte survival pathway involving the alpha-1A receptor subtype and ERK activation exists in vitro. However, data in vivo are limited. Here we tested A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a selective imidazoline agonist for the alpha-1A. A61603 was the most potent alpha-1-agonist in activating ERK in neonatal rat ventricular myocytes. A61603 activated ERK in adult mouse ventricular myocytes and protected the cells from death caused by the anthracycline doxorubicin. A low dose of A61603 (10 ng/kg/d) activated ERK in the mouse heart in vivo, but did not change blood pressure. In male mice, concurrent subcutaneous A61603 infusion at 10 ng/kg/d for 7 days after a single intraperitoneal dose of doxorubicin (25 mg/kg) increased survival, improved cardiac function, heart rate, and cardiac output by echocardiography, and reduced cardiac cell necrosis and apoptosis and myocardial fibrosis. All protective effects were lost in alpha-1A-knockout mice. In female mice, doxorubicin at doses higher than in males (35–40 mg/kg) caused less cardiac toxicity than in males. We conclude that the alpha-1A-selective agonist A61603, via the alpha-1A adrenergic receptor, prevents doxorubicin cardiomyopathy in male mice, supporting the theory that alpha-1A adrenergic receptor agonists have potential as novel heart failure therapies.

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Section: Resultssupporting

confidence: 69%

An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice

et al. 2017

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“…The expression of cardiac hypertrophy markers a-MHC, β-MHC, and BNP was examined in RL-14 cells to further confirm the protective effects of DoxQ on cardiomyocytes. Chronic treatment with doxorubicin causes cardiotoxicity that may progress to cardiac myopathy and heart failure via multiple cellular pathways [49]. Maayah et al reported that treatment of RL-14 cells with doxorubicin caused cardiotoxicity manifested by induction in the expression of β-MHC/α-MHC genes [50].…”

Section: Discussionmentioning

confidence: 99%

“…Maayah et al reported that treatment of RL-14 cells with doxorubicin caused cardiotoxicity manifested by induction in the expression of β-MHC/α-MHC genes [50]. Furthermore, Chen et al showed that doxorubicin enhanced the protein expression of BNP and β-MHC while reducing the expression of α-MHC in a rat model [49]. These observations are supported by our findings in this study as doxorubicin induced the expression of β-MHC more than α-MHC (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mechanistically elucidating the in vitro safety and efficacy of a novel doxorubicin derivative

Alrushaid

Zhao

Sayre

et al. 2017

Drug Deliv. and Transl. Res.

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Doxorubicin is an effective anticancer drug; however, it is cardiotoxic and has poor oral bioavazilability. Quercetin is a plant-based flavonoid with inhibitory effects on P-glycoprotein (P-gp) and CYP3A4 and also antioxidant properties. To mitigate these therapeutic barriers, DoxQ, a novel derivative of doxorubicin, was synthesized by conjugating quercetin to doxorubicin. The purpose of this study is to mechanistically elucidate the in vitro safety and efficacy of DoxQ. Drug release in vitro and cellular uptake by multidrug-resistant canine kidney (MDCK-MDR) cells were quantified by HPLC. Antioxidant activity, CYP3A4 inhibition, and P-gp inhibitory effects were examined using commercial assay kits. Drug potency was assessed utilizing triple-negative murine breast cancer cells, and cardiotoxicity was assessed utilizing adult rat and human cardiomyocytes (RL-14). Levels of reactive oxygen species and gene expression of cardiotoxicity markers, oxidative stress markers, and CYP1B1 were determined in RL-14. DoxQ was less cytotoxic to both rat and human cardiomyocytes and retained anticancer activity. Levels of ROS and markers of oxidative stress demonstrate lower oxidative damage induced by DoxQ compared to doxorubicin. DoxQ also inhibited the expression and catalytic activity of CYP1B1. Additionally, DoxQ inhibited CYP3A4 and demonstrated higher cellular uptake by MDCK-MDR cells than doxorubicin. DoxQ provides a novel therapeutic approach to mitigate the cardiotoxicity and poor oral bioavailability of doxorubicin. The cardioprotective mechanism of DoxQ likely involves scavenging ROS and CYP1B1 inhibition, while the mechanism of improving the poor oral bioavailability of doxorubicin is likely related to inhibiting CYP3A4 and P-gp.

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“…The procedure and protocol for transthoracic echocardiography were based on our previous report . Transthoracic echocardiography (Vevo 2100; VisualSonics, Toronto, ON, Canada) was performed in each group prior to and at day 60 after doxorubicin treatment by an animal cardiologist blind to the experimental design.…”

Section: Methodsmentioning

confidence: 99%

The cardioprotective effect of melatonin and exendin‐4 treatment in a rat model of cardiorenal syndrome

Chua

Lee

Chiang

et al. 2016

Journal of Pineal Research

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We investigated the cardioprotective effect of melatonin (Mel) and exendin-4 (Ex4) treatment in a rat model of cardiorenal syndrome (CRS). Adult male SD rats (n=48) were randomly and equally divided into sham control (SC), dilated cardiomyopathy (DCM) (doxorubicin 7 mg/kg i.p. every five days/4 doses), CRS (defined as DCM+CKD) only, CRS-Mel (20 mg/kg/d), CRS-Ex4 (10 μg/kg/d), and CRS-Mel-Ex4 groups. In vitro results showed protein expressions of oxidative stress (NOX-1/NOX-2/oxidized protein), DNA/mitochondrial damage (γ-H2AX/cytosolic cytochrome c), apoptosis (cleaved caspase-3/PARP), and senescence (β-galactosidase cells) biomarkers were upregulated, whereas mitochondrial ATP level was decreased in doxorubicin/p-cresol-treated H9c2 cells that were revised by Mel and Ex4 treatments (all P<.001). By day 60, LVEF was highest in the SC and lowest in the CRS, significantly lower in the DCM than in other treatment groups, lower in the CRS-Mel and CRS-Ex4 than in the CRS-Mel-Ex4, and lower in the CRS-Mel than in the CRS-Ex4, whereas LV chamber size and histopathology score showed a pattern opposite to that of LVEF among all groups (all P<.001). Plasma creatinine level was highest in the CRS and lowest in the SC and progressively decreased from the CRS-Mel, CRS-Ex4, CRS-Mel-Ex4 to DCM (P<.0001). Protein expressions of inflammation (TNF-α/NF-κB/MMP-2/MMP-9/IL-1β), apoptosis/DNA damage (Bax/c-caspase-3/c-PARP/γ-H2AX), fibrosis (Smad3/TGF-β), oxidative stress (NOX-1/NOX-2/NOX-4/oxidized protein), cardiac hypertrophy/pressure overload (BNP/β-MHC), and cardiac integrity (Cx43/α-MHC) biomarkers in LV myocardium showed an opposite pattern compared to that of LVEF among all groups (all P<.001). Fibrotic area, DNA damage (γ-H2AX /53BP1 CD90 /XRCC1 CD90 ), and inflammation (CD14 /CD68 ) biomarkers in LV myocardium displayed a pattern opposite to that of LVEF among all groups (all P<.001). Combined melatonin and exendin-4 treatment suppressed CRS-induced deterioration of LVEF and LV remodeling.

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Early Administration of Carvedilol Protected against Doxorubicin-Induced Cardiomyopathy

Cited by 38 publications

References 37 publications

An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice

An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice

Mechanistically elucidating the in vitro safety and efficacy of a novel doxorubicin derivative

The cardioprotective effect of melatonin and exendin‐4 treatment in a rat model of cardiorenal syndrome

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