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.

PURPOSE: 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.

METHODS: 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.

RESULTS: 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.

An increase in oxidative stress is suggested to be the main cause in Doxorubicin (Dox) -induced cardiotoxicity. However, there is now evidence that activation of inducible nitric oxide synthase (iNOS) and nitrosative stress are also involved. The role of Vitamin C (Vit C) in the regulation of nitric oxide synthase (NOS) and reduction of nitrosative stress in Dox-induced cardiotoxicity is unknown. The present study investigated the effects of Vit C in the mitigation of Dox-induced changes in the levels of nitric oxide (NO), NOS activity, protein expression of NOS isoforms and nitrosative stress as well as cytokines TNFα and IL-10 in isolated cardiomyocytes. Cardiomyocytes isolated from adult Sprague Dawley rats were segregated into four groups: i) control; ii) Vit C (25 µM); iii) Dox (10 µM); and iv) Vit C + Dox. Dox caused significant increase in the generation of superoxide radical (O2(-)), peroxynitrite andNO and these effects of Dox were blunted by Vit C. Dox increased the expression of iNOS and altered protein expression as well as activation of endothelial NOS (eNOS). These changes were prevented by Vit C. Dox-induced increase in the ratio of monomeric/dimeric eNOS, promoting the production of O2(-), which was prevented by Vit C by increasing the stability of dimeric form of eNOS. Vit C protected against Dox-induced increase in TNFα as well as a reduction in IL-10. These results suggest that Vit C provides cardioprotection by reducing oxidative/nitrosative stress and inflammation via a modulation of Dox-induced increase in the NO levels and NOS activity.

INTRODUCTION:Doxorubicin (DOX) is a widely used chemotherapeutic agent with known cardiotoxic properties, while calorie restriction (CR) and exercise have well-documented cardioprotective effects. No studies have investigated the effects of CR alone or the combined effects of CR and exercise on DOX cardiotoxicity.

METHODS:Rats were divided into 4 groups based on their food intake (ad libitum or CR) and activity (sedentary or voluntary wheel running [WR]). After completing a 16-week treatment, animals received either DOX (15 mg/kg) or saline (SAL) and cardiac function was measured 5 days after treatment. Chromatography was used to quantify left ventricular DOX accumulation.

RESULTS:Left ventricular developed pressure (LVDP), end systolic pressure (ESP), and left ventricular maximal rate of pressure development (dP/dt) were significantly higher in the CR + DOX group when compared with DOX. Fractional shortening, LVDP, ESP, dP/dt, and dP/dtwere significantly higher in the CR + WR + DOX group compared with the DOX group. In addition, the CR + WR + DOX group showed significantly higher LVDP and ESP compared with the WR + DOX group. DOX accumulation in the heart was 5-fold lower ( P<.05) in the CR + WR + DOX group compared with the DOX group.

CONCLUSION:This is the first study to demonstrate that CR can reduce cardiac DOX accumulation, and confirms the protective role of CR against DOX-induced cardiac dysfunction. Our data also show that combining a known cardioprotective intervention, exercise training, with CR results in additive benefits in the protection against DOX cardiotoxicity.

Previous studies have indicated that MD-fraction (MDF), in which the active component is beta 1,6-glucan with beta 1,3-branches, has anti-tumor activity as an oral agent and acts as an immune adjuvant. Since some other beta glucans appear to promote mobilization of hematopoietic stem cells, the effects of a beta glucan extract from the Maitake mushroom "MD-fraction" on hematopoietic stem cells were examined in a colony forming assay. Here we report for the first time that MDF has a dose response effect on mouse bone marrow cells (BMC) hematopoiesis in vitro. Using the Colony Forming Unit (CFU) assay to detect formation of granulocyte-macrophage (CFU-GM) colonies, and the XTT cytotoxicitiy assay to measure BMC viability, the data showed that the addition of MDF significantly enhanced the development of CFU-GM in a dose range of 50-100 microg/ml (p<0.004). The mechanism of action included significant increase of nonadherent BMC viability, which was observed at MDF doses of 12.5-100 microg/ml (p<0.005). In the presence of Doxorubicin (DOX), MDF promoted BMC viability and protected CFU-GM from DOX induced toxicity. In addition, MDF treatment promoted the recovery of CFU-GM colony formation after BMC were pretreated with DOX. These studies provided the first evidence that MDF acts directly in a dose dependent manner on hematopoietic BMC and enhances BMC growth and differentiation into colony forming cells.

OBJECTIVE:To demonstrate the morphological changes in number of seminiferous tubules that are produced by anthracycline doxorubicin on the testes of mice.

METHODS:This experimental study was conducted at Dow University of Health Sciences, Karachi, from March to August 2012, and comprised male mice aged up to five weeks. The mice were separated into 3 equal groups: A, B and C. Each animal was treated with normal saline 1ml intraperitoneal in group A, doxorubicin alone in group B and doxorubicin + vitamin C in group C. At the end of the study, animals were sacrificed and the testes were kept in Bouin's fluid and tissue processing and staining were done. SPSS 16 was used for data analysis.

RESULTS:Of the 30 mice, there were 10(33.3%) in each group. The overall mean age was 5±1 weeks. The mean number of tubules was 20.28±3.29 in group A, 9.39±3.01 in group B and 18.56±2.82 in group C. The mean diameter of seminiferous tubules of testes was 218.26 ± 7.45µm in group A, 123.96±11.84 in group B and 180.86±12.13 in group C (p<0.001). Co-administration of vitamin C with doxorubicin significantly reduced (p<0.001) the seminiferous epithelial damage compared to doxorubicin group.

CONCLUSIONS:The antioxidant vitamin C had a significant role in ameliorating the damage of testes induced by doxorubicin.

The purpose of this study was to assess the synergistic effect of polydatin and vitamin C on attenuating cardiotoxicity induced by doxorubicin (DOX) in rats. Polydatin could significantly increase the activity of SOD and the heart rate, attenuate myocardial pathological damage, decrease MDA content, slightly increase arterial pressure and GSH-Px activity, reduce intervals of QRS, QT and ST, and lower FFA content. The combination of polydatin and vitamin C could significantly increase arterial pressure and heart rate, decrease QRS interval and slightly reduce ST and QT intervals, significantly attenuate myocardial pathological damage, increase the activities of GSH-Px,T-SOD, Na(+) K(+) -ATPase and Ca(2+) Mg(2+) -ATPase, and elevate PCr and ATP contents, slightly increase ADP and TAN contents and PCr/ATP, and significantly decrease the contents of MDA and FFA, when compared with those in the DOX group. Meanwhile, the improvement effects on FFA content, the activities of ATPase and SOD and contents of ATP and TAN in combination group were more obvious than those in polydatin group; and the improvement effects on arterial pressure, heart rate, interval of QRS, GSH-Px activity, and MDA, ADP and PCr contents in combination group were slightly obvious when compared with those in polydatin group. In addition, the mRNA expression levels of AMPK-α2 and PPAR-α were slightly improved in combination group. The results illustrate that the combination of polydatin and vitamin C has the ability to enhance the myocardial protective effects by its antioxidative effect and improving energy metabolism. This article is protected by copyright. All rights reserved.

BACKGROUND:Preclinical evidence shows that short-term fasting (STF) protects healthy cells against side effects of chemotherapy and makes cancer cells more vulnerable to it. This pilot study examines the feasibility of STF and its effects on tolerance of chemotherapy in a homogeneous patient group with early breast cancer (BC).

METHODS:Eligible patients had HER2-negative, stage II/III BC. Women receiving (neo)-adjuvant TAC (docetaxel/doxorubicin/cyclophosphamide) were randomized to fast 24 h before and after commencing chemotherapy, or to eat according to the guidelines for healthy nutrition. Toxicity in the two groups was compared. Chemotherapy-induced DNA damage in peripheral blood mononuclear cells (PBMCs) was quantified by the level ofγ-H2AX analyzed by flow cytometry.

RESULTS:Thirteen patients were included of whom seven were randomized to the STF arm. STF was well tolerated. Mean erythrocyte- and thrombocyte counts 7 days post-chemotherapy were significantly higher (P = 0.007, 95 % CI 0.106-0.638 and P = 0.00007, 95 % CI 38.7-104, respectively) in the STF group compared to the non-STF group. Non-hematological toxicity did not differ between the groups. Levels ofγ-H2AX were significantly increased 30 min post-chemotherapy in CD45 + CD3- cells in non-STF, but not in STF patients.

CONCLUSIONS:STF during chemotherapy was well tolerated and reduced hematological toxicity of TAC in HER2-negative BC patients. Moreover, STF may reduce a transient increase in, and/or induce a faster recovery of DNA damage in PBMCs after chemotherapy. Larger studies, investigating a longer fasting period, are required to generate more insight into the possible benefits of STF during chemotherapy.

TRIAL REGISTRATION:ClinicalTrials.gov: NCT01304251 , March 2011.

Increase in oxidative/nitrosative stress is one of the mechanisms associated with the development of cardiotoxicity due to doxorubicin (Dox), a potent chemotherapy drug. Previously, we reported mitigation of Dox-induced oxidative/nitrosative stress and apoptosis by vitamin C (Vit C) in isolated cardiomyocytes. In the present in vivo study in rats, we investigated the effect of prophylactic treatment with Vit C on Dox-induced apoptosis, inflammation, oxidative/nitrosative stress, cardiac dysfunction, and Vit C transporter proteins. Dox (cumulative dose: 15 mg/kg) in rats reduced systolic and diastolic cardiac function and caused structural damage. These changes were associated with a myocardial increase in reactive oxygen species, reduction in antioxidant enzyme activities, increased expression of apoptotic proteins, and inflammation. Dox also caused an increase in the expression of proapoptotic proteins Bax, Bnip-3, Bak, and caspase-3. An increase in oxidative/nitrosative stress attributable to Dox was indicated by an increase in superoxide, protein carbonyl formation, lipid peroxidation, nitric oxide (NO), NO synthase (NOS) activity, protein nitrosylation, and inducible NOS protein expression. Dox increased the levels of cardiac proinflammatory cytokines TNF-α, IL-1β, and IL-6, whereas the expression of Vit C transporter proteins (sodium-ascorbate cotransporter 2 and glucose transporter 4) was reduced. Prophylactic and concurrent treatment with Vit C prevented all these changes and improved survival in the Vit C + Dox group. Vit C also improved Dox-mediated systolic and diastolic dysfunctions and structural damage. These results suggest a cardioprotective role of Vit C in Dox-induced cardiomyopathy by reducing oxidative/nitrosative stress, inflammation, and apoptosis, as well as improving Vit C transporter proteins.This in vivo study provides novel data that vitamin C improves cardiac structure and function in doxorubicin-induced cardiomyopathy by reducing oxidative/nitrosative stress, apoptosis, and inflammation along with upregulation of cardiac vitamin C transporter proteins. The latter may have a crucial role in improving antioxidant status in this cardiomyopathy.