Prevention Of Doxorubicin-induced Cardiotoxicity Research Articles

Effects of metformin and donepezil on the prevention of doxorubicin-induced cardiotoxicity in breast cancer: a randomized controlled trial

Doxorubicin (DOX) causes deleterious cardiotoxicity. We aimed to investigate the protective roles of metformin and donepezil against DOX-induced cardiotoxicity. In this randomized-controlled trial, 143 female breast cancer patients were enrolled. Metformin (n = 43), donepezil (n = 52), or placebo (n = 48) were prescribed during DOX treatment. The primary endpoint was a proportion of patients with high sensitivity troponin-I (hsTnI) more than the 99th percentile value (> 15.6 ng/L) after DOX treatment. The secondary outcomes were the changes in the hsTnI, N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and peripheral blood mononuclear cells analysis for mitochondrial respiration. Baseline characteristics were similar between the groups. The primary endpoint occurred in 58.54% of metformin group, 76.92% in donepezil group, and 69.77% in placebo group (p = 0.215). The level of hsTnI increased after receiving DOX with subsequent decline in LVEF and GLS. Metformin and donepezil did not attenuate hsTnI elevation, LVEF or GLS reduction. There was no significant change in NT-proBNP level. Mitochondrial respiratory dysfunction was observed in the placebo and donepezil groups. However, metformin preserved mitochondrial respiration during DOX therapy. In conclusion, co-treatment with metformin or donepezil did not prevent myocardial injury. Metformin had a favorable mitochondrial outcome and warranted future studies.

Abstract 4771: Prevention of doxorubicin-induced cardiotoxicity by benfotiamine

Abstract Anthracyclines such as daunorubicin and doxorubicin (DOX) are currently used as chemotherapeutic agents in the prevention of various cancers including breast cancer, lung cancer, leukemia, and lymphoma. Although, anthracyclines are successful in controlling various cancers growth, the major drawback is the unwanted cardiotoxicity. Specifically, high doses of DOX used for the therapy of advanced cancers could cause life threating conditions. Therefore, specific interventions are required to decrease the cardiac toxicity associated with the DOX. Benfotiamine, a lipid soluble vitamin B1 derivative has shown be a potent anti-oxidant and anti-inflammatory agent. However, the efficacy of benfotiamine in the prevention of cardiotoxicity associated with the anthracyclines is not known. In this study, we examined the effect of benfotiamine in the prevention of DOX-induced cytotoxicity in the human umbilical vascular endothelial cells (HUVECs). Treatment of HUVECs with DOX caused significant endothelial cells death and benfotiamine in a concentration-dependent manner prevented the dox-induced endothelial cell death. Further, benfotiamine prevents the DOX-induced apoptosis in endothelial cells by preventing the activation of caspase-3. Benfotiamine also prevents DOX-induced reactive oxygen species generation. Our results also indicate that benfotiamine regulates DOX-induced expression of pro-apoptotic mediators such as BAD, phosphor-P53, and pro-caspase-3, and anti-apoptotic mediators such as BCL-2, BCL-x, IAPs, and HSP and others such as FADD, DR5, and SMAC/diablo. We plan to further explore how benfotiamine prevents DOX-induced cardiotoxicity using human cardiac myocytes and mouse models. Thus, based on our cell culture studies, benfotiamine through its potent anti-oxidative property could prevent endothelial cytotoxicity and suggests that it could be further developed as adjuvant therapy in controlling cardiotoxicity associated with the anthracycline chemotherapy. Citation Format: Justin R. Taylor, Kyra Harames. Prevention of doxorubicin-induced cardiotoxicity by benfotiamine. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4771.

Abstract 11469: Effects of Metformin and Donepezil on the Prevention of Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patient: A Randomized Controlled Trial

Introduction: Cardiotoxicity from doxorubicin (DOX) is the most concerning adverse event. Although data from preclinical studies showed that metformin and donepezil prevented myocardial injury and preserved mitochondrial function against DOX-induced cardiotoxicity, the beneficial effects of these drugs in clinical trial have not been established. Hypothesis: Oral administration with metformin or donepezil prior receiving DOX prevents DOX-induced cardiotoxicity in breast cancer patients. Methods: In this double-blind, placebo-controlled trial. We randomly assigned 111 female breast cancer patients to receive oral metformin 2000 mg (n=40), donepezil 10 mg (n=31), or placebo (n=40), once daily 1 day prior to DOX and continued during DOX treatment. Blood samples were obtained at baseline, after chemotherapy cycle 2 and 4. The primary outcome was the change of troponin-I (trop-I) from baseline. The secondary outcomes were the change in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline, and mitochondrial function in the peripheral blood mononuclear cells. Results: Baseline characteristics were similar between the groups, mean age was 51.93±10.45 years. The mean trop-I changed from baseline were 29.97±4.59 pg/ml in placebo group, 31.07±7.28 pg/ml in metformin group (p = 0.90 vs. placebo) and 30.97±5.07 pg/ml in donepezil group (p = 0.88 vs. placebo). The changes of NT-proBNP level and mitochondrial oxidative stress were comparable between placebo vs. metformin or donepezil groups. However, donepezil significantly decreased mitochondrial mass and mitochondrial maximal respiration after chemotherapy (Figure). Conclusion: In breast cancer patients undergoing chemotherapeutic treatment with DOX, metformin and donepezil did not prevent myocardial injury. Treatment with donepezil resulted in the decrease in mitochondrial mass and maximal respiration following chemotherapy that might caution its use in breast cancer.

Abstract 9710: Prevention of Doxorubicin-Induced Cardiotoxicity Through Targeted Degradation of Topoisomerase 2b

Introduction: Doxorubicin-induced cardiotoxicity is a serious complication of cancer therapy recognized 40 years ago and remains to be a major clinical challenge today. Doxorubicin poisons topoisomerase 2a to kill cancer cells, whereas doxorubicin induces cardiotoxicity through topoisomerase 2b. When topoisomerase 2b was genetically deleted in the cardiomyocytes of adult mice, doxorubicin-induced cardiomyopathy can be prevented. Hypothesis: Pharmacological depletion of topoisomerase 2b in cardiac tissue could prevent doxorubicin-induced cardiomyopathy. Methods: Cell lines were treated with dexrazoxane (100 μM) for different time intervals with or without the proteasome inhibitor MG132 (10 μM). Cell lysates were immunoblotted with anti-topoisomerase 2a or 2b antibodies or anti-actin. Mice were injected with dexrazoxane (100 mg/kg IP) and cardiac tissues were analyzed for expression of topoisomerase 2b over time using western blot analysis. To study the effect of dexrazoxane pre-treatment on doxorubicin-induced chronic heart failure, C57BL/6 mice (n=7) were pre-treated with dexrazoxane (100 mg/kg IP) 8 hours before doxorubicin (5 mg/kg IP). Single injection of dexrazoxane (n=6), doxorubicin (n=8), or saline control (n=6) were also administered to three different cohorts of mice. This protocol was repeated weekly for 5 weeks. Pre-treatment and post-treatment cardiac MRI were obtained to evaluate the change in left ventricular ejection fraction. Results: Dexrazoxane induced a ubiquitin-dependent degradation of topoisomerase 2b, but not 2a in cell lines. In dexrazoxane-treated mice, topoisomerase 2b was not detectable 8 hours after dexrazoxane administration, but gradually returned to normal levels by 48 hours. Dexrazoxane pre-treatment 8 hours before doxorubicin prevented doxorubicin-induced reduction in ejection fraction as determined by cardiac MRI in a chronic heart failure model. Conclusions: Targeted degradation of topoisomerase 2b by dexrazoxane prevented doxorubicin-induced cardiotoxicity. Through selective degradation of topoisomerase 2b, but not 2a, doxorubicin's tumoricidal activity is preserved. This preventive strategy will be tested in a prospective clinical trial in breast cancer patients.

Prevention of doxorubicin-induced Cardiotoxicity by pharmacological non-hypoxic myocardial preconditioning based on Docosahexaenoic Acid (DHA) and carvedilol direct antioxidant effects: study protocol for a pilot, randomized, double-blind, controlled trial (CarDHA trial)

BackgroundAnthracycline-induced cardiotoxicity (AIC), a condition associated with multiple mechanisms of damage, including oxidative stress, has been associated with poor clinical outcomes. Carvedilol, a β-blocker with unique antioxidant properties, emerged as a strategy to prevent AIC, but recent trials question its effectiveness. Some evidence suggests that the antioxidant, not the β-blocker effect, could prevent related cardiotoxicity. However, carvedilol’s antioxidant effects are probably not enough to prevent cardiotoxicity manifestations in certain cases. We hypothesize that breast cancer patients taking carvedilol as well as a non-hypoxic myocardial preconditioning based on docosahexaenoic acid (DHA), an enhancer of cardiac endogenous antioxidant capacity, will develop less subclinical cardiotoxicity manifestations than patients randomized to double placebo.Methods/designWe designed a pilot, randomized controlled, two-arm clinical trial with 32 patients to evaluate the effects of non-hypoxic cardiac preconditioning (DHA) plus carvedilol on subclinical cardiotoxicity in breast cancer patients undergoing anthracycline treatment. The trial includes four co-primary endpoints: changes in left ventricular ejection fraction (LVEF) determined by cardiac magnetic resonance (CMR); changes in global longitudinal strain (GLS) determined by two-dimensional echocardiography (ECHO); elevation in serum biomarkers (hs-cTnT and NT-ProBNP); and one electrocardiographic variable (QTc interval). Secondary endpoints include other imaging, biomarkers and the occurrence of major adverse cardiac events during follow-up. The enrollment and follow-up for clinical outcomes is ongoing.DiscussionWe expect a group of anthracycline-treated breast cancer patients exposed to carvedilol and non-hypoxic myocardial preconditioning with DHA to show less subclinical cardiotoxicity manifestations than a comparable group exposed to placebo.Trial registrationISRCTN registry, ID: ISRCTN69560410. Registered on 8 June 2016.

The Role of Metoprolol and Enalapril in the Prevention of Doxorubicin-induced Cardiotoxicity in Lymphoma Patients.

Anthracyclines, such as doxorubicin, though widely used in anticancer therapy, they are associated with cardiotoxic side-effects. The aim of this trial was to investigate long-term follow-up cardiotoxicity findings in patients treated with doxorubicin and concomitant metoprolol or enalapril 10 years earlier. Overall, 147 patients were randomized into the treatment arms. A total of 125 patients treated with doxorubicin without evidence of heart disease at the start of chemotherapy were analyzed. They were followed-up for up to 10 years after treatment start. A total of 47 patients completed the follow-up and 21 patients died, none due to cardiotoxicity events. Clinical signs of heart failure were not seen in any patients and no statistically significant differences between baseline and 10-year findings were seen for echocardiographic variables. No evidence of long-term cardiotoxicity was seen and nor metoprolol or enalapril offered an additional benefit.

Comparative Study of the Protective Effect of Metformin and Sitagliptin against Doxorubicin-Induced Cardiotoxicity in Rats

Background and aim: Cancer patients treated with doxorubicin are at high risk to develop cardiotoxicity and hyperglycemia. The present study was designed to compare the effect of the two anti-hyperglycemia drugs; metformin and Sitagliptin, in the prevention of doxorubicin-induced cardiotoxicity in rats. Methods: Cardiotoxicity was induced in male Wistar rats by intraperitoneal injection of cumulative dose of doxorubicin (15 mg/kg over 3 weeks). Metformin or sitagliptin was administrated orally concomitant with intraperitoneal doxorubicin for 3 weeks. Mean body weight, systolic blood pressure, electrocardiographic changes, serum lactate dehydrogenase and creatine kinase-myocardium band, blood glucose and cardiac malondialdhyde level, cardiac histopathological examination and in vitro cardiac contractility in response to isoprenaline were be assessed. Results: Doxorubicin induced marked cardiotoxicity evidenced by significant deterioration in body weight, systolic blood pressure and heart rate, elevation of ST segment, prolongation of QT interval, elevation in the serum level of creatine kinase-myocardiac band and lactate dehydrogenase, blood glucose and cardiac malondialdhyde level and reduced in vitro cardiac contractility in response to isoprenaline compared to control untreated rats. These changes were associated with histopathological evidence of cardiotoxicity. Administration of either metformin or sitagliptin with doxorubicin resulted in significant improvement in all tested parameters compared with doxorubicin treated rats. Metformin treated rats showed more significant improvement in systolic blood pressure, ST segment elevation, serum enzymes, cardiac malondialdhyde, histopathological finding and in vitro cardiac contractility than sitagliptin treated rats. Conclusion: The present study showed that metformin ameliorated doxorubicin-induced cardiotoxicity better than sitagliptin.

Evaluation of the phytochemical composition and protective activities of methanolic extracts of Centaurea borysthenica and Centaurea daghestanica (Lipsky) Wagenitz on cardiomyocytes treated with doxorubicin

ABSTRACTCentaurea L. is a genus of the family Asteraceae that comprises over 600 taxa. Representatives of the Centaurea genus were used as natural medications for many diseases. Methanolic-aqueous extracts from aerial parts of two Centaurea species: C. borysthenica Gruner and C. daghestanica (Lipsky) Wagenitz were studied for their polyphenolic composition and potential protective effect on cardiomyocytes treated with doxorubicin. Effectiveness of doxorubicin in cancer therapy is limited by a dose-dependent cardiotoxicity. Oxidative stress is a widely recognized mechanism of this phenomenon. One of the most important strategies has been an application of drug together with antioxidant agents. A cardioprotective effect of selected extracts of Centaurea species was suspected in this study. Cell viability, oxidative stress, and mitochondrial membrane potential analyses showed protective activity of the methanolic extract of C. borysthenica and C. daghestanica on rat cardiomyocytes treated with doxorubicin. Although C. borysthenica is more effective as a cardiomyocyte protective agent, in higher concentrations it weakened the drug activity. C. daghestanica extract did not change the doxorubicin efficacy in the evaluated experiment. Interestingly, both tested extracts were cytotoxic for myeloma cells. The detected antioxidant activity of the studied extracts can be used in the prevention of doxorubicin-induced cardiotoxicity.

Prevention of doxorubicin-induced cardiotoxicity by melatonin

Anthracyclines, such as doxorubicin and daunorubicin, are highly effective anticancer agents. Cardiotoxicity made by these agents develops as a complication of the cancer chemotherapy. Melatonin, the chief secretory product of the pineal gland, was recently found to be a free radical scavenger and antioxidant. We decided to evaluate the tissue-protective effect of melatonin against myocardial toxic effects of doxorubicin in six groups of rats. Rats were given doxorubicin (Dx) (45 mg/kg dose) and melatonin (MEL) (10 mg/kg), first doxorubicin and then melatonin (DM), first melatonin and then doxorubicin (MD). The degree of cardiac muscle cell alterations were examined either histologically (mean total score technique) or biochemically. In doxorubicin-treated group, malondialdehyde (MDA) levels of the heart tissue were significantly increased, glutathione (GSH) levels were decreased compared to the control rats. In the group in which first doxorubicin and then melatonin was given, MDA levels were significantly decreased and glutathione (GSH) levels were increased compared to the doxorubicin-treated group. During ultrastructural analysis, in doxorubicin-treated group, cellular edema, mitochondrial deformation, decreased glycogen stores, and disordered myofibrillary structure were observed. In contrast, in first doxorubicin and then melatonin-treated group, normal cellular structure was observed. But, first melatonin and then doxorubicin-treated group was not significantly preserved from the doxorubicin-induced changes. By preventing lipid peroxidation and myocardial lesions, melatonin may be highly effective in protecting against doxorubicin-induced cardiotoxicity.

NADPH-cytochrome-P450 reductase promotes hydroxyl radical production by the iron complex of ADR-925, the hydrolysis product of ICRF-187 (dexrazoxane).

ICRF-187 (dexrazoxane) is currently in clinical trials as a cardioprotective agent for the prevention of doxorubicin-induced cardiotoxicity. ICRF-187 likely acts through its strongly metal ion-binding rings-opened hydrolysis product ADR-925 by removing iron from its complex with doxorubicin or by chelating free iron. The ability of NADPH-cytochrome-P450 reductase to promote hydroxyl radical formation by iron complexes of ADR-925 and EDTA was compared by EPR spin trapping. The iron-EDTA complex produced hydroxyl radicals at six times the rate that the iron-ADR-925 complex did. The aerobic oxidation of ferrous complexes of ADR-925, its tetraacid analog, EDTA and DTPA was followed spectrophotometrically. The iron(II)-ADR-925 complex was aerobically oxidized 700 times slower than was the EDTA complex. It is concluded that even though ADR-925 does not completely eliminate iron-based hydroxyl radical production, it likely protects by preventing site-specific hydroxyl radical damage by the iron-doxorubicin complex.

Dexrazoxane in the Prevention of Doxorubicin-Induced Cardiotoxicity

To review doxorubicin-induced cardiotoxicity and to evaluate the use of dexrazoxane in its prevention. All animal and human reports involving doxorubicin-induced cardiac adverse effects were searched using MEDLINE combined with a fan search of relevant papers. Animal, in vitro cellular, and human data are thoroughly reviewed with particular emphasis on doxorubicin-induced cardiotoxicity, including clinical manifestations, risk factors, and mechanisms of toxicity. The role of dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity is reviewed, including mechanism of effect, animal data, and human trials. Anthracyclines are associated with a cumulative, dose-dependent, irreversible cardiomyopathy that can lead to congestive heart failure and death. The incidence of cardiotoxicity rises sharply at a total lifetime dose of more than 550 mg/m2. Through its semiquinone metabolite, doxorubicin appears to generate superoxide anion and superhydroxide free radicals with iron as a cofactor. Because of poor myocardial concentrations of superoxide dismutase, catalase, and glutathione peroxidase, these free radicals cause extensive lipid peroxidation and mitochondrial destruction. Dexrazoxane is hydrolyzed to its active form intracellularly and binds iron to prevent the formation of superhydroxide radicals, thus preventing mitochondrial destruction. The effect of dexrazoxane on the prevention of doxorubicin-induced cardiotoxicity is impressive in both animal and human studies. Further research is needed to clearly demonstrate the effect dexrazoxane has on the antitumor effects of combination chemotherapy while defining optimal dosing strategies to minimize myelosuppression and maximize cardioprotection.

Prevention of doxorubicin-induced cardiotoxicity by recombinant interleukin-1 in hamsters. Doxorubicin cardiotoxicity and interleukin-1.

The major factor contributing to doxorubicin (DXR)-induced cardiotoxicity is the insufficiency of antioxidant defense mechanisms. As a model of acute cardiotoxicity with DXR, ten-week-old golden hamsters were given DXR (5 mg/kg) intravenously, and the toxicity was investigated by monitoring ECG changes. Complete A-V block and cardiac arrest on the ECG were observed in DXR-treated hamsters. DXR-induced edema and fragmentation of myofibrils were observed by electron-micrograph. Pretreatment with interleukin-1 beta (10 or 1 microgram/body) 12 or 24 hrs before prevented these changes, but pretreatment with tumor necrosis factor alpha had no effect.