Glutamine regulation of doxorubicin accumulation in hearts versus tumors in experimental rats

Тодорова, Валентина; Kaufmann, Yihong; Hennings, Leah; Klimberg, V. Suzanne

doi:10.1007/s00280-009-1165-8

Cited by 14 publications

(19 citation statements)

References 58 publications

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“…Specifically, single glutamine treatment markedly improves host cardiac function, reduces plasma cTnI levels, preserves histological integrity, mitigates cardiomyocyte apoptosis, and lowers cardiac lipid peroxidation associated concomitant enhanced endogenous antioxidant defense. Our findings are supported by the studies from Todorova et al, 20,41 in which oral glutamine supplementation also improved cardiac function, reduced plasma cTnI levels, and preserved cardiac redox homeostasis in an acute DIC model in which mammary tumor-bearing rats received a single bolus dose of DOX at 12 mg/kg. However, of note, the functional, structural, and even transcriptional alterations observed in acute regimen models may not be applicable to patients in the clinic, who receive a considerably lower dose of DOX repeated over many weeks or months.…”

Section: Discussionsupporting

confidence: 87%

“…Female Fisher344 rats (Charles River Laboratories, Wilmington, MA) bearing syngeneic mammary adenocarcinoma xenograft treated with DOX were used as the drug-tumor model. 41 Rats were housed 2 per cage in a temperature- (22°C) and light-controlled (12-hour light) room; water and food were available for ad libitum consumption. A suspension of 1 × 10 6 rat mammary adenocarcinoma MatBIII cells (ATCC, Manassas, VA) was injected into the flank of female Fisher344 rats (3 months old, 130–150 g of body weight).…”

Section: Experimental Methodsmentioning

confidence: 99%

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Nutrition Modulation of Cardiotoxicity and Anticancer Efficacy Related to Doxorubicin Chemotherapy by Glutamine and ω‐3 Polyunsaturated Fatty Acids

Xue

Denkinger

Schlotzer

et al. 2015

J Parenter Enteral Nutr

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Background Doxorubicin (DOX) has been one of the most effective antitumor agents against a broad spectrum of malignancies. However, DOX-induced cardiotoxicity forms the major cumulative dose-limiting factor. Glutamine and ω-3 polyunsaturated fatty acids (PUFAs) are putatively cardioprotective during various stresses and/or have potential chemosensitizing effects during cancer chemotherapy. Methods Antitumor activity and cardiotoxicity of DOX treatment were evaluated simultaneously in a MatBIII mammary adenocarcinoma tumor-bearing rat model treated with DOX (cumulative dose 12 mg/kg). Single or combined treatment of parenteral glutamine (0.35 g/kg) and ω-3 PUFAs (0.19 g/kg eicosapentaenoic acid and 0.18 g/kg docosahexaenoic acid) was administered every other day, starting 6 days before chemotherapy initiation until the end of study (day 50). Results Glutamine alone significantly prevented DOX-related deterioration of cardiac function, reduced serum cardiac troponin I levels, and diminished cardiac lipid peroxidation while not affecting tumor inhibition kinetics. Single ω-3 PUFA treatment significantly enhanced antitumor activity of DOX associated with intensified tumoral oxidative stress and enhanced tumoral DOX concentration while not potentiating cardiac dysfunction or increasing cardiac oxidative stress. Intriguingly, providing glutamine and ω-3 PUFAs together did not consistently confer a greater benefit; conversely, individual benefits on cardiotoxicity and chemosensitization were mostly attenuated or completely lost when combined. Conclusions Our data demonstrate an interesting differentiality or even dichotomy in the response of tumor and host to single parenteral glutamine and ω-3 PUFA treatments. The intriguing glutamine × ω-3 PUFA interaction observed draws into question the common assumption that there are additive benefits of combinations of nutrients that are beneficial on an individual basis.

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Section: Discussionsupporting

confidence: 87%

Section: Experimental Methodsmentioning

confidence: 99%

Nutrition Modulation of Cardiotoxicity and Anticancer Efficacy Related to Doxorubicin Chemotherapy by Glutamine and ω‐3 Polyunsaturated Fatty Acids

Xue

Denkinger

Schlotzer

et al. 2015

J Parenter Enteral Nutr

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“…These include: administration of antioxidants [15], scavengers of peroxynitrite [7], iron chelating agents [16] and glutamate [17], inhibition of endocannabinoids [6], [18], treatment with factors such as erythropoietin [19] or granulocyte stimulating factor [20] and abrogation of p53 activity via global knockdown [21] or chemical inhibition [22] approaches. More recently, Zhu et al have shown that blocking p53 in a cardiomyocyte restricted manner was sufficient to prevent systolic dysfunction and reduction in cardiac mass induced by acute Dox treatment for seven days [23].…”

Section: Introductionmentioning

confidence: 99%

Cardiomyocyte Specific Ablation of p53 Is Not Sufficient to Block Doxorubicin Induced Cardiac Fibrosis and Associated Cytoskeletal Changes

et al. 2011

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Doxorubicin (Dox) is an anthracycline used to effectively treat several forms of cancer. Unfortunately, the use of Dox is limited due to its association with cardiovascular complications which are manifested as acute and chronic cardiotoxicity. The pathophysiological mechanism of Dox induced cardiotoxicity appears to involve increased expression of the tumor suppressor protein p53 in cardiomyocytes, followed by cellular apoptosis. It is not known whether downregulation of p53 expression in cardiomyocytes would result in decreased rates of myocardial fibrosis which occurs in response to cardiomyocyte loss. Further, it is not known whether Dox can induce perivascular necrosis and associated fibrosis in the heart. In this study we measured the effects of acute Dox treatment on myocardial and perivascular apoptosis and fibrosis in a conditional knockout (CKO) mouse model system which harbours inactive p53 alleles specifically in cardiomyocytes. CKO mice treated with a single dose of Dox (20 mg/kg), did not display lower levels of myocardial apoptosis or reactive oxygen and nitrogen species (ROS/RNS) compared to control mice with intact p53 alleles. Interestingly, CKO mice also displayed higher levels of interstitial and perivascular fibrosis compared to controls 3 or 7 days after Dox treatment. Additionally, the decrease in levels of the microtubule protein α-tubulin, which occurs in response to Dox treatment, was not prevented in CKO mice. Overall, these results indicate that selective loss of p53 in cardiomyocytes is not sufficient to prevent Dox induced myocardial ROS/RNS generation, apoptosis, interstitial fibrosis and perivascular fibrosis. Further, these results support a role for p53 independent apoptotic pathways leading to Dox induced myocardial damage and highlight the importance of vascular lesions in Dox induced cardiotoxicity.

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“…We have used a rat model of DOX-induced cardiotoxicity, which resembles the physiological and histological findings in patients [89], [90], [91]. We have analyzed >22,000 transcripts in the hearts and PBMCs of rats 48 hours after a single dose (12 mg/kg) of DOX, similar to the single dose of DOX (often one of several doses over time) used in the treatment of human cancer (65–75 mg/m 2 ) [30].…”

Section: Discussionmentioning

confidence: 99%

“…The fluorescent properties of DOX were used to verify the equal concentrations of DOX in the blood and heart samples [33]. The fluorescent levels were expressed as µg/mg protein or µg/ml blood.…”

Section: Methodsmentioning

confidence: 99%

Transcriptome Profiling of Peripheral Blood Cells Identifies Potential Biomarkers for Doxorubicin Cardiotoxicity in a Rat Model

et al. 2012

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AimsDoxorubicin (DOX), a widely used anticancer agent, can cause an unpredictable cardiac toxicity which remains a major limitation in cancer chemotherapy. There is a need for noninvasive, sensitive and specific biomarkers which will allow identifying patients at risk for DOX-induced cardiotoxicity to prevent permanent cardiac damage. The aim of this study was to investigate whether the expression of specific genes in the peripheral blood can be used as surrogate marker(s) for DOX-induced cardiotoxicity.Methods/ResultsRats were treated with a single dose of DOX similar to one single dose that is often administered in humans. The cardiac and peripheral blood mononuclear cells (PBMCs) genome-wide expression profiling were examined using Illumina microarrays. The results showed 4,409 differentially regulated genes (DRG) in the hearts and 4,120 DRG in PBMC. Of these 2411 genes were similarly DRG (SDRG) in both the heart and PBMC. Pathway analysis of the three datasets of DRG using Gene Ontology (GO) enrichment analysis and Ingenuity Pathways Analysis (IPA) showed that most of the genes in these datasets fell into pathways related to oxidative stress response and protein ubiquination. IPA search for potential eligible biomarkers for cardiovascular disease within the SDRG list revealed 188 molecules.ConclusionsWe report the first in-depth comparison of DOX-induced global gene expression profiles of hearts and PBMCs. The high similarity between the gene expression profiles of the heart and PBMC induced by DOX indicates that the PBMC transcriptome may serve as a surrogate marker of DOX-induced cardiotoxicity. Future directions of this research will include analysis of PBMC expression profiles of cancer patients treated with DOX-based chemotherapy to identify the cardiotoxicity risk, predict DOX-treatment response and ultimately to allow individualized anti-cancer therapy.

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Glutamine regulation of doxorubicin accumulation in hearts versus tumors in experimental rats

Abstract: These data indicate that GLN supplement is able to reduce DOX-induced cardiac damage and thus to enhance DOX therapeutic effectiveness.

Cited by 14 publications

References 58 publications

Nutrition Modulation of Cardiotoxicity and Anticancer Efficacy Related to Doxorubicin Chemotherapy by Glutamine and ω‐3 Polyunsaturated Fatty Acids

Nutrition Modulation of Cardiotoxicity and Anticancer Efficacy Related to Doxorubicin Chemotherapy by Glutamine and ω‐3 Polyunsaturated Fatty Acids

Cardiomyocyte Specific Ablation of p53 Is Not Sufficient to Block Doxorubicin Induced Cardiac Fibrosis and Associated Cytoskeletal Changes

Transcriptome Profiling of Peripheral Blood Cells Identifies Potential Biomarkers for Doxorubicin Cardiotoxicity in a Rat Model

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