Thrombopoietin Protects Against In Vitro and In Vivo Cardiotoxicity Induced by Doxorubicin

Li, Karen; Sung, Rita Yn Tz; Huang, Wei Zhe; Yang, Mei; Pong, Nga Hin; Lee, Shuk Man; Chan, Wood Yee; Zhao, Hai-Lu; To, Man Yin; Fok, Tai Fai; Li, Chi Kong; Wong, Yuek Oi; Ng, Pak Cheung

doi:10.1161/circulationaha.105.560250

Cited by 134 publications

(118 citation statements)

References 40 publications

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“…Recent investigations revealed unexpected effects of hematopoietic cytokines on DOX-induced cardiotoxicity; we reported erythropoietin, 6 whereas another group reported thrombopoietin, 7 prevented cardiac dysfunction in DOXinduced cardiomyopathy in mice. More recently, Hou et al reported preventive effects of granulocyte colony-stimulating factor (G-CSF) on progressive worsening of cardiac function in DOX-induced cardiomyopathy in rats.…”

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confidence: 74%

Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy

Takemura

et al. 2007

Laboratory Investigation

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It is not well-known yet how granulocyte colony-stimulating factor (G-CSF) affects nonischemic cardiomyopathy, though its beneficial effects on acute myocardial infarction are well-established. We hypothesize that G-CSF beneficially might affect nonischemic cardiomyopathy through the direct cardioprotective effects. Here, we show that a single injection of doxorubicin (DOX, 15 mg/kg) induced left ventricular dilatation and dysfunction in mice within 2 weeks, and that these effects were significantly attenuated by human recombinant G-CSF (100 mg/kg/day for 5 days). G-CSF also protected hearts against DOX-induced cardiomyocyte atrophy/degeneration, fibrosis, inflammatory cell infiltration and down regulation of GATA-4 and sarcomeric proteins, myosin heavy chain, troponin I and desmin, both in vivo and in vitro. Cardiac cyclooxygenase-2 was upregulated and G-CSF receptor was downregulated in DOX-induced cardiomyopathy, but both of those effects were largely reversed by G-CSF. No DOX-induced apoptotic effects were seen, nor were there any changes in tumor necrosis factor-a or transforming growth factor-b1 levels. Among downstream mediators of G-CSF receptor signaling, DOX-induced cardiomyopathy involved inactivation of extracellular signal-regulated protein kinase (ERK); the ERK inactivation was reversed by G-CSF. Inhibition of ERK activation, but not cyclooxygenase-2 inhibition, completely abolished beneficial effect of G-CSF on cardiac function. G-CSF did not promote differentiation of bone marrow cells into cardiomyocytes according to the experiment using green fluorescent protein-chimeric mice, and inhibition of CXCR4 þ cell homing using AMD3100 did not diminish the effect of G-CSF. Finally, G-CSF was also effective when administered after cardiomyopathy was established. In conclusion, these findings imply the therapeutic usefulness of G-CSF mainly through restoring ERK activation against DOX-induced nonischemic cardiomyopathy.

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confidence: 74%

Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy

Takemura

et al. 2007

Laboratory Investigation

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“…On the other hand, this same cell line has been used as a model to investigate the protective effect of several compounds against Dox-induced cardiotoxicity. Among such compounds, carvedilol (Spallarossa et al 2004), rosmarinic acid , plantainoside D (Kim et al 2007), or thrombopoietin (Li et al 2006) are particular examples.…”

Section: Discussionmentioning

confidence: 99%

Morphological alterations induced by doxorubicin on H9c2 myoblasts: nuclear, mitochondrial, and cytoskeletal targets

et al. 2008

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Doxorubicin (Dox) is a very potent antineoplastic agent used against several types of cancer, despite a cumulative cardiomyopathy that reduces the therapeutic index for treatment. H9c2 myoblast cells have been used as an in vitro model to study biochemical alterations induced by Dox treatment on cardiomyocyte cells. Despite the extensive work already published, few data are available regarding morphological alterations of H9c2 cells during Dox treatment. The purpose of the present work was to evaluate Doxinduced morphological alterations in H9c2 myoblasts, focusing especially on the nuclei, mitochondria, and structural fibrous proteins. Treatment of H9c2 cell with low concentrations of Dox causes alterations in fibrous structural proteins including the nuclear lamina and sarcomeric cardiac myosin, as well as mitochondrial depolarization and fragmentation, membrane blebbing with cell shape changes, and phosphatidylserine externalization. For higher Dox concentrations, more profound alterations are evident, including nuclear swelling with disruption of nuclear membrane structure, mitochondrial swelling, and extensive cytoplasm vacuolization. The results obtained indicate that Dox causes morphological alterations in mitochondrial, nuclear, and fibrous protein structures in H9c2 cells, which are dependent on the drug concentration. Data obtained with the present study allow for a better characterization of the effects of Dox on H9c2 myoblasts, used as a model to study Dox-induced cardiotoxicity. The results obtained also provide new and previously unknown targets that can contribute to understand the mechanisms involved in the cardiotoxicity of Dox.

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“…Potential clinical use of the protective effect of formaldehyde releasing prodrugs was tested in the frequently used Dox-induced toxicity mice model (Li et al, 2006;Lien et al, 2006) . Three parameters confirmed the protective effects of AN-7 against Doxinduced toxicity: abolition of Dox-induced increase in the level of serum LDH, attenuation of Dox-induced loss in body weight and reduced mortality.…”

Section: Discussionmentioning

confidence: 99%

Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity

et al. 2007

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Formaldehyde has been previously shown to play a dominant role in promoting synergy between doxorubicin (Dox) and formaldehyde-releasing butyric acid (BA) prodrugs in killing cancer cells. In this work, we report that these prodrugs also protect neonatal rat cardiomyocytes and adult mice against toxicity elicited by Dox. In cardiomyocytes treated with Dox, the formaldehyde releasing prodrugs butyroyloxymethyl diethylphosphate (AN-7) and butyroyloxymethyl butyrate (AN-1), but not the corresponding acetaldehyde-releasing butyroyloxydiethyl phosphate (AN-88) or butyroyloxyethyl butyrate (AN-11), reduced lactate dehydrogenase leakage, prevented loss of mitochondrial membrane potential (DCm) and attenuated upregulation of the proapoptotic gene Bax. In Dox-treated mice, AN-7 but not AN-88 attenuated weight-loss and mortality, and increase in serum lactate dehydrogenase. These findings show that BA prodrugs that release formaldehyde and augment Dox anticancer activity also protect against Dox cardiotoxicity. Based on these observations, clinical applications of these prodrugs for patients treated with Dox warrant further investigation.

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Thrombopoietin Protects Against In Vitro and In Vivo Cardiotoxicity Induced by Doxorubicin

Cited by 134 publications

References 40 publications

Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy

Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy

Morphological alterations induced by doxorubicin on H9c2 myoblasts: nuclear, mitochondrial, and cytoskeletal targets

Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity

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