Positive cardioprotective effects of Topoisomerase II poison, LS1, in doxorubicin treatment

The purpose of this study was to determine whether (1) sodium nitrate (SN) treatment progressed or alleviated doxorubicin (DOX)-induced cachexia and muscle wasting; and (2) if a more-clinically relevant low-dose metronomic (LDM) DOX treatment regimen compared to the high dosage bolus commonly used in animal research, was sufficient to induce cachexia in mice. Six-week old male Balb/C mice (n = 16) were treated with three intraperitoneal injections of either vehicle (0.9% NaCl; VEH) or DOX (4 mg/kg) over one week. To test the hypothesis that sodium nitrate treatment could protect against DOX-induced symptomology, a group of mice (n = 8) were treated with 1 mM NaNO3 in drinking water during DOX (4 mg/kg) treatment (DOX + SN). Body composition indices were assessed using echoMRI scanning, whilst physical and metabolic activity were assessed via indirect calorimetry, before and after the treatment regimen. Skeletal and cardiac muscles were excised to investigate histological and molecular parameters. LDM DOX treatment induced cachexia with significant impacts on both body and lean mass, and fatigue/malaise (i.e. it reduced voluntary wheel running and energy expenditure) that was associated with oxidative/nitrostative stress sufficient to induce the molecular cytotoxic stress regulator, nuclear factor erythroid-2-related factor 2 (NRF-2). SN co-treatment afforded no therapeutic potential, nor did it promote the wasting of lean tissue. Our data re-affirm a cardioprotective effect for SN against DOX-induced collagen deposition. In our mouse model, SN protected against LDM DOX-induced cardiac fibrosis but had no effect on cachexia at the conclusion of the regimen.

Doxorubicin (DOX) is a widely used chemotherapeutic agent known for its potent anticancer effects; however, its clinical utility is limited due to severe cardiotoxicity. The present study investigates the cardioprotective potential of peonidin against DOX-induced myocardial injury in Wistar rats. Wistar rats (155-180 g) were divided into four groups such as normal control with no treatment, DOX treatment, DOX with 200 mg/kg of peonidin and DOX with 400 mg/kg of peonidin administered subcutaneously (15 mg/kg) on the 8th and 9th days to induce cardiotoxicity. Peonidin was orally administered for seven days before DOX treatment. Blood samples were collected for biochemical analysis and histopathological and electrophysiological assessments were performed to evaluate myocardial damage and inflammation. DOX administration results in significant cardiac dysfunction, as evidenced by prolonged ST interval, decreased R wave amplitude, increased left ventricular end-diastolic pressure (LVEDP) and decreased left ventricular systolic pressure (LVSP). Elevated levels of cardiac biomarkers (LDH, CK and troponin) and inflammatory mediators (IL-6 and TNF-α) further confirm myocardial injury. Peonidin pre-treatment demonstrates a dose-dependent cardioprotective effect, with the 400 mg/kg dose showing significant improvements in ST interval, R wave amplitude, LVSP and ± dp/dtmax. Biochemical analysis reveals a substantial reduction in LDH, CK and troponin levels in the 400 mg/kg group. Histopathological examination further confirms reduced necrosis and preserved myocardial integrity in peonidin-treated rats. It was concluded that peonidin exhibits potent cardioprotective effects against DOX-induced myocardial injury through antioxidative, anti-inflammatory and membrane-stabilizing mechanisms.

Back ground: Doxorubicin is a very effective anticancer therapy of the anthracycline's family used in many pediatric and adult cancers. However, due to severe cardiotoxicity adverse effect, the uses of doxorubicin are limited. Metformin reducing basal and
 postprandial glucose levels. Metformin has a good treatment efficacy and safety profile in treatment of T2DM in conjunction with lifestyle modification. Metformin have a cardioprotective effect in addition to reducing basal and postprandial levels of glucose by decreasing the production of reactive oxygen species, maintaining energy homeostasis and apoptosis regulation by its activation of adenosine monophosphate-activated protein kinase. 
 Method: Thirty-six white male rabbits randomly divided to six groups, each comprising of six rabbits. 1- Control group injected 2 ml saline single dose intraperitoneally. 2- Metformin group 300 mg/kg/daily for 14 days orally. 3- Acute doxorubicin induction group 16 mg/ kg intraperitoneally as a single dose. 4- Chronic doxorubicin induction group 4mg/kg intraperitoneally twice a week for two weeks. 5- Metformin+ acute doxorubicin induction group 16 mg/kg intraperitoneally single dose and Metformin 300 mg/kg/daily for 14 days orally, three days before doxorubicin treatment. 6- Metformin + chronic doxorubicin induction group 4 mg/kg intraperitoneally, twice a week for two weeks and Metformin 300 mg/kg/daily for 14 days orally, three days before doxorubicin treatment. 
 Result: our results revealed the treatment with metformin significantly (p < 0.05) reduced the serum level of troponin I and MMP2 in Metformin+ acute doxorubicin induction and Metformin + chronic doxorubicin induction groups in comparison with the acute doxorubicin and chronic doxorubicin groups.
 Conclusion: From these results in this study, we can conclude that metformin has a cardioprotective effect against doxorubicin induced cardiotoxicity in acute and also the chronic induction by decreasing serum level of troponin I and MMP2.

Back ground: Doxorubicin is a very effective anticancer therapy of the anthracycline's family used in many pediatric and adult cancers. However, due to severe cardiotoxicity adverse effect, the uses of doxorubicin are limited. Metformin reducing basal and postprandial glucose levels. Metformin has a good treatment efficacy and safety profile in treatment of T2DM in conjunction with lifestyle modification. Metformin have a cardioprotective effect in addition to reducing basal and postprandial levels of glucose by decreasing the production of reactive oxygen species, maintaining energy homeostasis and apoptosis regulation by its activation of adenosine monophosphate-activated protein kinase. Method: Thirty-six white male rabbits randomly divided to six groups, each comprising of six rabbits. 1- Control group injected 2 ml saline single dose intraperitoneally. 2- Metformin group 300 mg/kg/daily for 14 days orally. 3- Acute doxorubicin induction group 16 mg/ kg intraperitoneally as a single dose. 4- Chronic doxorubicin induction group 4mg/kg intraperitoneally twice a week for two weeks. 5- Metformin+ acute doxorubicin induction group 16 mg/kg intraperitoneally single dose and Metformin 300 mg/kg/daily for 14 days orally, three days before doxorubicin treatment. 6- Metformin + chronic doxorubicin induction group 4 mg/kg intraperitoneally, twice a week for two weeks and Metformin 300 mg/kg/daily for 14 days orally, three days before doxorubicin treatment. Result: our results revealed the treatment with metformin significantly (p < 0.05) reduced the serum level of troponin I and MMP2 in Metformin+ acute doxorubicin induction and Metformin + chronic doxorubicin induction groups in comparison with the acute doxorubicin and chronic doxorubicin groups. Conclusion: From these results in this study, we can conclude that metformin has a cardioprotective effect against doxorubicin induced cardiotoxicity in acute and also the chronic induction by decreasing serum level of troponin I and MMP2.

Numerous methods have been used to minimize the cardiotoxic effects of the chemotherapeutic agent doxorubicin (DOX), and most have had limited success. Chronic endurance exercise has been shown to protect against DOX cardiotoxicity, but little is known regarding the effects of acute exercise on DOX-induced cardiac dysfunction. The purpose of this study was to determine the effects of a single bout of acute endurance exercise on the cardiac dysfunction associated with DOX treatment. Male Sprague-Dawley rats either performed an acute exercise bout on a motorized treadmill for 60 minutes at a maximal speed of 25 m/min with a 5% grade (EX) or remained sedentary (SED) 24 hours before receiving either a 15-mg/kg DOX bolus dose or saline (SAL). Cardiac function was then analyzed 5 days post injection using a Langendorff isolated perfused heart model. In addition, myocardial lipid peroxidation was analyzed as an indicator of oxidative stress. Doxorubicin treatment alone (SED+DOX) promoted a significant decline in end-systolic pressure (-35%), left ventricular developed pressure (-59%), and the maximal rate of left ventricular pressure development (-43%) as well as a 45% increase in lipid peroxidation products when compared with SED+SAL (P<.05). Acute exercise 24 hours before DOX treatment, however, had a cardioprotective effect, as end-systolic pressure, left ventricular developed pressure, and the maximal rate of left ventricular pressure development were significantly higher in EX+DOX compared with SED+DOX (P<.05) and EX+DOX had similar levels of lipid peroxidation products as SED+SAL CONCLUSIONS: An acute exercise bout performed 24 hours before DOX treatment protected against cardiac dysfunction, and this exercise-induced cardioprotection may partly be explained by a reduction in the generation of reactive oxygen species.

Herba leonurine attenuates doxorubicin-induced apoptosis in H9c2 cardiac muscle cells

Varenicline as a cardioprotective agent against doxorubicin-induced toxicity: A study on apoptotic, TLR4/NF-κB, and inflammasome/caspase-1/IL-1β pathway modulation in a rat model.

Keeping the Heart Fitm2 during Chemotherapy.

e23057 Background: Empagliflozin (EMPA), a selective inhibitor of the sodium glucose co-transporter 2 (SGLT2), reduces the risk of hospitalization for heart failure or cardiovascular death in type 2 diabetic patients. We aimed to study if EMPA could have cardioprotective and anti-inflammatory effects in Doxorubicin (DOXO) - Induced cardiotoxicity. Methods: we tested the effects of EMPA alone or in combination with DOXO in HL-1 adult cardiomyocytes evaluating: mitochondrial viability, lipid peroxidation, Leukotriene-B4 expression, p65-NF-κB activation and Interleukin 1β, 8 and 6 secretion. To evaluate cardiac function, Global Longitudinal Strain (GLS) were measured using 2D speckle tracking echocardiography in C57BL6 mice pretreated with EMPA (10 mg/kg/day) per os for 3 days. EMPA was then administered for additional 7 days, alone and in combination with DOXO (2.25 mg/kg/day ip). Cardiac lysates were processed for analysis of pro-inflammatory Interleukins. Results: EMPA, co-incubated with DOXO, is able to increase the cardiomyocyte viability of 33,6 and 82,3 % at 100 and 500 nM, respectively (compared to only DOXO treated cells). EMPA inhibits the lipid peroxidation by decreasing MDA and 4-HNA production of around 23,6 and 28,7 %, at 100 nM and of 47,8 and 52,1 % at 500 nM, respectively, compared to untreated cells. Moreover, EMPA has anti-inflammatory activity with a reduction of Leukotriene B4 expression and p65-NFkb activation of 58,4 and 64,3 % at 500 nM, respectively (compared to only DOXO treated cells). EMPA also decreased the expression of Interleukin 1β (of 28,5 and 68,8 %), Interleukin-8 (of 21,2 and 57,3 % ) and Interleukin-6 (of 28,1 and 49,8 %) at 100 and 500 nM, respectively, compared to only DOXO exposed cells. Preclinically, after 7 days with DOXO, GLS decreased. Interestingly, in mice treated with EMPA+DOXO, EMPA prevents the GLS’s reduction : GLS was 19.24 ± 1.5 (p &lt; 0,01) vs DOXO alone. In DOXO-EMPA groups, the heart IL-1β, IL-6 and IL-8 tissue extract were reduced of 48, 54,4 and 58,2 % compared to only DOXO groups. Conclusions: EMPA has strong anti-inflammatory and cardioprotective effects in DOXO-Induced cardiotoxicity and these effects are mainly mediated by a reduction of the lipid peroxidation, Leukotriene-B4 and NF-κB activation.

Cardiotoxicity from chemotherapy drugs is a major adverse effect of cancer chemotherapy, which strongly compromises therapeutic outcomes. The application of cardioprotective agents is an effective strategy to mitigate cardiotoxicity in the clinic. However, the effects of chemotherapeutic drugs and their doses, as well as the efficacy of cardioprotective agents on the function of cardiomyocytes, especially at different stages of cardiotoxicity, have not been well explored, partly owing to the lack of real-time functional parameters of cardiomyocytes after drug treatment. Herein, we constructed in vitro doxorubicin (DOX)-induced cardiotoxicity (DIC) models through culturing neonatal rat primary cardiomyocytes on polyacrylamide (PA) gels with a stiffness of around 20.0 kPa, and adding DOX at different concentrations to mimic the mild, moderate, and severe stages of chemotherapeutic drug-induced cardiotoxicity. We used scanning electrochemical microscopy (SECM) to monitor the respiratory activity, contraction frequency, and membrane permeability of cardiomyocytes after DOX treatment in situ. The SECM results obtained demonstrated that 0.25-5.0 μM DOX dosages led to decreased respiratory activity and contraction frequency, accompanied by increased membrane permeability of cardiomyocytes. We also used SECM to evaluate the cardioprotective effect of bisoprolol (a clinically approved β-blocker for cardiovascular diseases) on cardiomyocytes under DOX treatment and obtained its optimal protective efficacy for 1.0 μM DOX-treated cardiomyocytes. Our work provides in situ functional information on living cardiomyocytes under chemotherapeutic drug and cardioprotective agent treatments, contributing to a better understanding of the pathological features and prevention strategies of chemotherapy-induced cardiotoxicity.

Doxorubicin (DOX) has been widely employed to treat cancer, particularly solid tumors and hematological malignancies, owing to its high efficacy; however, chemotherapy has been indicated to be cardiotoxic and induce adverse effects, including mitochondrial dysfunction and DNA damage, which limits its application. The mitochondria-associated protein leucine-rich pentatricopeptide repeat-containing (LRPPRC) has been reported to serve critical regulatory roles in physiological processes via regulating mitochondrial function. The aim of the present study was to investigate the possible protective effects of LRPPRC against DOX-induced cardiac injury. In a DOX-induced cardiotoxicity model in H9C2 cells, LRPPRC was indicated to be transcriptionally upregulated and stabilize Bcl-2 and Bax. LRPPRC overexpression exhibited protective effects against proliferation and both apoptotic and non-apoptotic cell death following DOX treatment, but not under normal conditions. It was additionally observed that overexpressed LRPPRC reversed the decreases in ATP synthesis, mitochondrial mass and transcriptional activity, which were induced by DOX exposure. Overexpressed LRPPRC also decreased the accumulation of reactive oxygen species (ROS) under DOX treatment and inhibited cell death to a similar extent as N-acetyl-L-cysteine, which is a known ROS scavenger, indicating that LRPPRC potentially exerts protective effects via inhibiting ROS accumulation. Moreover, LRPPRC overexpression protected H9C2 cells against oxidative stress induced by H2O2, which also indicated its ROS-scavenging function. The present study demonstrated for the first time, to the best of our knowledge, that DOX-induced LRPPRC may exert cardioprotective effects via inhibiting ROS accumulation, thereby maintaining mitochondrial function.

Cardioprotective action of the aqueous extract of Terminalia arjuna bark against toxicity induced by doxorubicin

Cardioprotective effects of zofenopril, a new angiotensin-converting enzyme inhibitor, on doxorubicin-induced cardiotoxicity in the rat

Doxorubicin causes cardiotoxicity and exercise intolerance. Pre-conditioning exercise training seems to prevent doxorubicin-induced cardiac damage. However, the effectiveness of the cardioprotective effects of exercise training concomitantly with doxorubicin treatment remains largely unknown. To determine whether low-to-moderate intensity aerobic exercise training during doxorubicin treatment would prevent cardiotoxicity and exercise intolerance, we performed exercise training concomitantly with chronic doxorubicin treatment in mice. Ventricular structure and function were accessed by echocardiography, exercise tolerance by maximal exercise test, and cardiac biology by histological and molecular techniques. Doxorubicin-induced cardiotoxicity, evidenced by impaired ventricular function, cardiac atrophy, and fibrosis. Exercise training did not preserve left ventricular ejection fraction or reduced fibrosis. However, exercise training preserved myocardial circumferential strain alleviated cardiac atrophy and restored cardiomyocyte cross-sectional area. On the other hand, exercise training exacerbated doxorubicin-induced body wasting without affecting survival. Finally, exercise training blunted doxorubicin-induced exercise intolerance. Exercise training performed during doxorubicin-based chemotherapy can be a valuable approach to attenuate cardiotoxicity.

Doxorubicin (DOX) is an anticancer agent for treating solid and soft tissue malignancies. However, the clinical use of DOX is restricted by cumulative, dose-dependent cardiotoxicity. Therefore, the present study aimed to assess the cardioprotective effects of P. ginseng C. A. Mey, febuxostat, and their combination against DOX-induced cardiotoxicity. Thirty-five Sprague Dawley male rats were used in this study. The animals were randomly divided into five groups, with seven rats per group. The control group received normal saline, the induced group received DOX only, and the treated group received P. ginseng, febuxostat, and their combination before DOX treatment. Biomarkers of acute cardiac toxicity were assessed in each group. Results showed that treatment with the combination of febuxostat and P. ginseng before DOX led to a significant improvement in the biomarkers of acute DOX-induced cardiotoxicity. In conclusion, the combination of P. ginseng and febuxostat produced more significant cardioprotective effects against DOX-induced cardiotoxicity when compared to either P. ginseng or febuxostat when used alone. The potential mechanism of this combination was mainly mediated by the anti-inflammatory and antioxidant effects of P. ginseng and febuxostat.