Doxorubicin-induced Oxidative Stress Research Articles

Prevention of doxorubicin-induced haematotoxicity by turmeric in Wistar rats

Doxorubicin is a known anticancer drug used in treatment of various cancers including leukemias, lymphomas, soft-tissue sarcomas and solid tumors. Doxorubicin exerts its toxicity on the blood by causing bone marrow suppression, myelosuppression, pronounced marrow depression and bone marrow depletion, and hypoplasia This study investigated the effect of turmeric on the haematological parameters in doxorubicin-induced oxidative stress in Wistar rats. 54 adult Wistar rats were divided into 9 groups of six animals each. Group 1 animals served as control (normal saline), group 2 animals served as negative control, and received doxorubicin, group 3 animals were given doxorubicin and turmeric, group 4 animals received doxorubicin and vitamin C, group 5 animals received doxorubicin and vitamin E, group 6 animals received doxorubicin, vitamins C and turmeric, group 7 animals received doxorubicin, vitamin E and turmeric, while group 8 animals received doxorubicin, vitamin C and vitamin E and finally, group 9 animals receive doxorubicin, vitamin C, vitamin E and turmeric. The experiment lasted for 28 days and blood samples were collected from each animal from the various groups for haematological assay. Doxorubicin caused a significant decrease in the serum levels of white blood cell count, neutrophil count, lymphocyte count, monocyte count, platelet count, red blood cell count, hemoglobin concentration, hematocrit and mean corpuscular volume. These changes were prevented by turmeric alone or in combined concomitant administration with vitamins C and or E and doxorubicin

In vivo and In vitro Antioxidant Activities of Aqueous and Ethanol Stem Bark Extracts of Vitex doniana on Doxorubicin-induced Oxidative Stress in Rats

Background: Oxidative stress is involved in the pathogenesis of hypertension, myocardial ischemia-reperfusion injury, atherosclerosis, muscular dystrophy, aging and other associated diseases. Vitex doniana is used in Adamawa, northern Nigeria to treat oxidative stress associated diseases. However, the antioxidative effects of the plant have not been scientifically examined in oxidative stress experimental animal models. The aim of this study is to investigate the in vitro and in vivo antioxidant activities of aqueous and ethanol stem bark extracts of Vitex doniana in oxidative stress model of rats.
 Methods: The study used 35 adult albino rats weighing 175 ± 25 g, of which 30 were induced with oxidative stress by intraperitoneal injection of doxorubicin (10 mg/kg) for three consecutive days. Animals were treated by oral administration of silymarin (100 mg/kg) and Vitex doniana aqueous or ethanol extract (100 mg/kg and 200 mg/kg) for 14 consecutive days before they were sacrificed on the 15th day and blood was analyzed for biochemical indices of oxidative stress.
 Results: The results of the phytochemistry showed the presence of alkaloids, tannins, flavonoids, steroids, phenols, saponins, terpenoids, glycosides: and total flavonoids (52.70 ± 1.60 mg/ml and 75.40 ± 0.80 mg/ml), total phenols (21.45 ± 1.54 mg/ml and 26.50 ± 1.22 mg/ml) for aqueous and ethanol stem bark extracts respectively. The extracts scavenged DPPH radical, reduced Fe3+ and inhibited lipid peroxidation. Doxorubicin significantly (p<0.05) lowered the levels of SOD, CAT, GR and TAS and significantly (p<0.05) but, increased the level of LPO. Oral treatment with Vitex doniana extracts significantly (p<0.05) increased the activities of CAT, GR, SOD and TAS while LPO was significantly (p<0.05) lowered. Vitex doniana stem bark extracts significantly (p<0.05) improved the biochemical derangements observed in the induced untreated animals in comparable manner to that of Silymarin.
 Conclusion: The present study provides the scientific rationale for the use of Vitex doniana stem bark in traditional medicine and has a viable antioxidative capacity both in vitro and in vivo.

Evaluation of Anti-Oxidants Potential of Turmeric, Vitamins C and E in Doxorubicin-Induced Oxidative Stress in Wistar Rats

Evaluation of Anti-Oxidants Potential of Turmeric, Vitamins C and E in Doxorubicin-Induced Oxidative Stress in Wistar Rats

EFFECT OF DOXORUBICIN-INDUCED OXIDATIVE STRESS ON CITRULLINE CONCENTRATION IN THE SMALL INTESTINAL MUCOSA AND PLASMA BLOOD IN RATS WITH NON-ALCOHOLIC STEATOHEPATITIS

The aim: Is to investigate the effect of doxorubicin-induced oxidative stress on plasma citrulline and citrulline concentration in the small intestinal (SI) mucosa of rats with non-alcoholic steatohepatitis (NASH). Materials and methods: The studies were carried out on 30 white non-linear adult rats, 15 (50%) males, 15 (50%) females, weighing 160-220 g. The rats were divided into three groups: І (n=10) – rats without NASH, received a standard diet, subsequently were injected with doxorubicin in cumulative dose of 15 mg/kg; ІI (n=10) – rats with NASH, received a high-calorie diet with doxorubicin injection similarly to group I; ІІІ (n=10) –control group, received a standard diet, were injected with placebo. In the SI mucosa, the levels of thiobarbituric acid reactive substances (TBARS), citrulline and catalase were determined. Also the level of plasma citrulline was analyzed. Results: Doxorubicin injection resulted in induction of oxidative stress in rats of group I and II, which was characterized by 2.1 (p=0.002) and 1.4 times (р=0.0059) increase in TBARS and in 3.4 (р=0.002), and 5.2 times (р=0.002) decrease in catalase activity respectively comparing with the control group. Simultaneously plasma citrulline level in group I and II was in 1.4 (р=0.0039) and 1,5 times (р=0.0039) respectively lower, compared to the control group. Conclusions: Doxorubicin-induced SI injury was associated with a significant decrease in plasma citrulline in rats regardless of NASH. The plasma citrulline could become an important marker in the assessment of the SI injury in clinical practice.

Prevention of doxorubicin-induced dyslipidaemia, plasma oxidative stress and electrolytes imbalance in Wistar rats by aqueous leaf-extracts of Chromolaena odorata and Tridax procumbens

This study investigated the ability of aqueous leaf-extracts of Chromolaena odorata and Tridax procumbens to modulate plasma biomarkers of oxidative stress, electrolytes, lipid profiles and atherogenic indices in doxorubicin treated rats. Doxorubicin was administered at 15 mg/kg body weight (intra-peritioneally, 48 h prior to sacrifice); metformin was administered daily at 250 mg/kg (orally, for 14 days); while both extracts were daily administered at 50, 75 and 100 mg/kg (orally, for 14 days). The plasma malondialdehyde, triglyceride, apolipoprotein B, total cholesterol, non-high density lipoproteins cholesterol, low density lipoproteins cholesterol and very low density lipoproteins cholesterol, calcium, chloride and sodium concentrations; atherogenic index of plasma, cardiac risk ratio, atherogenic coefficient and Castelli's risk index II of Test control were significantly (p<0.05) higher than those of all the other groups. However, their plasma ascorbic acid, reduced glutathione, high density lipoproteins cholesterol, potassium and magnesium concentrations were significantly (p<0.05) lower than those of all the other groups. In addition, the plasma catalase and superoxide dismutase activities of Test control were significantly (p<0.05) lower than those of the others. The above imply that the extracts have the ability to prevent doxorubicin-induced oxidative stress, dyslipidaemia and electrolytes imbalance. These results suggest that, at least in part, due to antioxidant and hypolipidaemic properties, aqueous extracts of T. procumbens and C. odorata leaves may potentially reduce the risk of doxorubicin-induced cardiovascular disorders.

Orosomucoid 1 Attenuates Doxorubicin-Induced Oxidative Stress and Apoptosis in Cardiomyocytes via Nrf2 Signaling.

Doxorubicin (DOX) is an effective anticancer drug, but its therapeutic use is limited by its cardiotoxicity. The principal mechanisms of DOX-induced cardiotoxicity are oxidative stress and apoptosis in cardiomyocytes. Orosomucoid 1 (ORM1), an acute-phase protein, plays important roles in inflammation and ischemic stroke; however, the roles and mechanisms of ORM1 in DOX-induced cardiotoxicity remain unknown. Therefore, in the present study, we aimed to investigate the function of ORM1 in cardiomyocytes experiencing DOX-induced oxidative stress and apoptosis. A DOX-induced cardiotoxicity animal model was established in C57BL/6 mice by administering an intraperitoneal injection of DOX (20 mg/kg), and the control group was intraperitoneally injected with the same volume of sterilized saline. The effects were assessed after 7 d. Additionally, H9c2 cells were stimulated with DOX (10 μM) for 24 h. The results showed decreased ORM1 and increased oxidative stress and apoptosis after DOX stimulation in vivo and in vitro. ORM1 overexpression significantly reduced DOX-induced oxidative stress and apoptosis in H9c2 cells. ORM1 significantly increased the expression of nuclear factor-like 2 (Nrf2) and its downstream protein heme oxygenase 1 (HO-1) and reduced the expression of the lipid peroxidation end product 4-hydroxynonenal (4-HNE) and the level of cleaved caspase-3. In addition, Nrf2 silencing reversed the effects of ORM1 on DOX-induced oxidative stress and apoptosis in cardiomyocytes. In conclusion, ORM1 inhibited DOX-induced oxidative stress and apoptosis in cardiomyocytes by regulating the Nrf2/HO-1 pathway, which might provide a new treatment strategy for DOX-induced cardiotoxicity.

Matrine attenuates pathological cardiac fibrosis via RPS5/p38 in mice.

Pathological cardiac fibrosis is a common feature in multiple cardiovascular diseases that contributes to the occurrence of heart failure and life-threatening arrhythmias. Our previous study demonstrated that matrine could attenuate doxorubicin-induced oxidative stress and cardiomyocyte apoptosis. In this study, we investigated the effect of matrine on cardiac fibrosis. Mice received aortic banding (AB) operation or continuous injection of isoprenaline (ISO) to generate pathological cardiac fibrosis and then were exposed to matrine lavage (200 mg·kg-1·d-1) or an equal volume of vehicle as the control. We found that matrine lavage significantly attenuated AB or ISO-induced fibrotic remodeling and cardiac dysfunction. We also showed that matrine (200 μmol/L) significantly inhibited the proliferation, migration, collagen production, and phenotypic transdifferentiation of cardiac fibroblasts. Mechanistically, matrine suppressed p38 activation in vivo and in vitro, and overexpression of constitutively active p38 completely abolished the protective effects of matrine. We also demonstrated that ribosomal protein S5 (RPS5) upregulation was responsible for matrine-mediated inhibition on p38 and fibrogenesis. More importantly, matrine was capable of ameliorating preexisting cardiac fibrosis in mice. In conclusion, matrine treatment attenuates cardiac fibrosis by regulating RPS5/p38 signaling in mice, and it might be a promising therapeutic agent for treating pathological cardiac fibrosis.

RETRACTED: Interleukin-22 deficiency alleviates doxorubicin-induced oxidative stress and cardiac injury via the p38 MAPK/macrophage/Fizz3 axis in mice

Several interleukin (IL) family members have been demonstrated to be involved in doxorubicin (DOX)-induced cardiac injury. This study aimed to investigate the role of IL-22 in DOX-induced cardiac injury and explore its possible mechanisms. In this study, mice were given DOX, and the cardiac expression and sources of IL-22 were determined. Then, IL-22 was knocked out to observe the effects on DOX-induced cardiac injury in mice. In addition, the p38 mitogen-activated protein kinase (MAPK) pathway was inhibited, macrophages were depleted and adoptively transferred, and Fizz3 was up-regulated in mice to explore the mechanisms. The results showed that cardiac IL-22 expression was significantly increased by DOX treatment and was mostly derived from cardiac macrophages. IL-22 knockout significantly reduced cardiac vacuolization and the expression of cardiomyocyte injury markers in both serum and left ventricular tissue and improved cardiac function in DOX-treated mice. In addition, IL-22 knockout reversed DOX-induced cardiac M1 macrophage/M2 macrophage imbalance, reduced oxidative stress and protected against cardiomyocyte apoptosis. p38 MAPK pathway inhibition with SB203580 and macrophage depletion further alleviated the above effects in DOX-treated IL-22-knockout mice. The effects were stronger IL-22-knockout mice with adoptive transfer of WT macrophages than in those with adoptive transfer of IL-22-knockout macrophages. Furthermore, increasing the expression of Fizz3 reduced cardiomyocyte apoptosis and alleviated cardiac dysfunction. Our results may suggest that IL-22 knockout alleviate DOX-induced oxidative stress and cardiac injury by inhibiting macrophage differentiation and thereby increasing the expression of Fizz3. Reductions in IL-22 expression may be beneficial for clinical chemotherapy in tumor patients.

Citrus sinensis and Vitis vinifera Protect Cardiomyocytes from Doxorubicin-Induced Oxidative Stress: Evaluation of Onconutraceutical Potential of Vegetable Smoothies.

The interest towards nutraceuticals able to counteract drug side effects is continuously growing in current chemotherapeutic protocols. In the present study, we demonstrated that smoothies containing mixtures of Citrus sinensis and Vitis vinifera L. cv. Aglianico N, two typical fruits of the Mediterranean diet, possess bioactive polyphenols that protect cardiomyocytes against doxorubicin-induced oxidative stress. The polyphenolic extracts isolated from Citrus sinensis- and Vitis vinifera-based functional smoothies were deeply characterized by Liquid Chromatography-Mass Spectrometry methods. Subsequently, the functional smoothies and relative mixtures were tested to verify their ability to affect cellular viability and oxidative stress parameters in embryonic cardiomyocyte cells (H9c2), and human breast adenocarcinoma cell line (MCF-7) exposed to doxorubicin. Interestingly, we found that the mix resulting from Citrus sinensis and Vitis vinifera association in ratio 1:1 was able to reduce cardiomyocytes damage induced by anthracyclines, without significantly interfering with the pro-apoptotic activity of the drug on breast cancer cells. These results point out the potential use of vegetable smoothies as adjuvants functional foods for chemotherapeutic anticancer protocols.

Human Amnion Membrane Proteins Prevent Doxorubicin-Induced Oxidative Stress Injury and Apoptosis in Rat H9c2 Cardiomyocytes.

Doxorubicin (DOX) is widely used as an effective chemotherapy agent in cancer treatment. Cardiac toxicity in cancer treatment with DOX demand urgent attention and no effective treatment has been established for DOX-induced cardiomyopathy. It has been well documented that human amniotic membrane proteins (AMPs), extracted from amnion membrane (AM), have antioxidant, anti-apoptotic, and cytoprotective properties. Therefore, in this study, we aimed to investigate the protective effects of AMPs against cardiotoxicity induced by DOX in cultured rat cardiomyocyte cells (H9c2). DOX-induced cell injury was evaluated using multi-parametric assay including thiazolyl blue tetrazolium bromide (MTT), the release of lactic dehydrogenase (LDH), intracellular Ca2+ , reactive oxygen species (ROS) levels, cellular antioxidant status, mitochondrial membrane potential (ΔΨm), malondialdehyde (MDA), and NF-κB p65 DNA-binding activity. Moreover, expression profiling of apoptosis-related genes (P53, Bcl-2, and Bax) and Annexin V by flow cytometry were used for cell apoptosis detection. It was shown that AMPs pretreatment inhibited the cell toxicity induced by DOX. AMPs effectively attenuated the increased levels of LDH, Ca2+ , ROS, and MDA and also simultaneously elevated the ΔΨm and antioxidant status such as superoxide dismutase (SOD) and Catalase (CAT) in pretreated H9c2 cardiomyocytes. Besides, the activity of NF-kB p65 was reduced and the p53 and Bax protein levels were inhibited in these myocardial cells subjected to DOX. These findings provide the first evidence that AMPs potently suppressed DOX-induced toxicity in cardiomyocytes through inhibition of oxidative stress and apoptosis. Thus, AMPs can be a potential therapeutic agent against DOX cardiotoxicity.

The Effects of Inhibition of MicroRNA-375 in a Mouse Model of Doxorubicin-Induced Cardiac Toxicity.

BackgroundDoxorubicin-induced myocardial toxicity is associated with oxidative stress, cardiomyocyte, apoptosis, and loss of contractile function. Previous studies showed that microRNA-375 (miR-375) expression was increased in mouse models of heart failure and clinically, and that inhibition of miR-375 reduced inflammation and increased survival of cardiomyocytes. This study aimed to investigate the effects and mechanisms of inhibition of miR-375 in a mouse model of doxorubicin-induced cardiac toxicity in vivo and in doxorubicin-treated rat and mouse cardiomyocytes in vitro.Material/MethodsThe mouse model of doxorubicin-induced cardiac toxicity was developed using an intraperitoneal injection of doxorubicin (15 mg/kg diluted in 0.9% saline) for eight days. Treatment was followed by a single subcutaneous injection of miR-375 inhibitor. H9c2 rat cardiac myocytes and adult murine cardiomyocytes (AMCs) were cultured in vitro and treated with doxorubicin, with and without pretreatment with miR-375 inhibitor.ResultsDoxorubicin significantly upregulated miR-375 expression in vitro and in vivo, and inhibition of miR-375 re-established myocardial redox homeostasis, prevented doxorubicin-induced oxidative stress and cardiomyocyte apoptosis, and activated the PDK1/AKT axis by reducing the direct binding of miR-375 to 3′ UTR of the PDK1 gene. Inhibition of PDK1 and AKT abolished the protective role of miR-375 inhibition on doxorubicin-induced oxidative damage.ConclusionsInhibition of miR-375 prevented oxidative damage in a mouse model of doxorubicin-induced cardiac toxicity in vivo and in doxorubicin-treated rat and mouse cardiomyocytes in vitro through the PDK1/AKT signaling pathway.

RETRACTED ARTICLE: Role of aminolevulinic acid synthase 1 in doxorubicin-induced oxidative stress to the ardiomyocyte.

Aminolevulinic acid synthase 1(ALAS 1) is the rate-limiting enzyme for heme synthesis, which is the essential source of intracellular oxidative stress under specific conditions. This study aimed to identify the role of ALAS1 in the oxidative injury of cardiomyocyte induced by doxorubicin. H9c2 cardiac myocytes were treated with a 5-μM concentration of doxorubicin for 24 h. ALAS1 small interfering RNA (siRNA) or rALAS1 plasmid was transfected into H9c2 cardiac myocytes to establish ALAS1 knockdown or over-expressing H9c2 cells. Apoptotic cells were detected using flow cytometric analysis. ALAS1 expression was detected by real-time PCR and western blot assay. The levels of heme were detected by ELISA. MitoSOX Red was introduced for detection of mitochondrial superoxide in H9c2 cells and was validated with confocal fluorescence microscopy. Doxorubicin increase the expression of ALAS1, and heme promotes the oxidative stress and apoptosis in H9c2 cardiac myocytes. Over-expression of ALAS1 can produce similar apoptotic effect on H9c2 cells with doxorubicin, although at a relatively low level. Inhibition of ALAS1 by ALAS1 siRNA decreased heme and mitochondrial superoxide levels, results in inhibition of doxorubicin-induced apoptosis. ALAS1 plays a pivotal role in the doxorubicin-induced oxidative stress and apoptosis in H9c2 cardiac myocytes.

Insulin-like growth factor II receptor-α is a novel stress-inducible contributor to cardiac damage underpinning doxorubicin-induced oxidative stress and perturbed mitochondrial autophagy.

Doxorubicin (DOX) is an anthracycline antibiotic commonly employed for the treatment of various cancers. However, its therapeutic uses are hampered by side effects associated with cumulative doses during the course of treatment. Whereas deregulation of autophagy in the myocardium has been involved in a variety of cardiovascular diseases, the role of autophagy in DOX-induced cardiomyopathy remains debated. Our earlier studies have shown that DOX treatment in a rat animal model leads to increased expression of the novel stress-inducible protein insulin-like growth factor II receptor-α (IGF-IIRα) in cardiac tissues, which exacerbated the cardiac injury by enhancing oxidative stress and p53-mediated mitochondria-dependent cardiac apoptosis. Through this study, we investigated the contribution of IGF-IIRα to dysregulation of autophagy in heart using both in vitro H9c2 cells (DOX treated, 1 µM) and in vivo transgenic rat models (DOX treated, 5 mg/kg ip for 6 wk) overexpressing IGF-IIRα specifically in the heart. We found that IGF-IIRα primarily localized to mitochondria, causing increased mitochondrial oxidative stress that was severely aggravated by DOX treatment. This was accompanied by a significant perturbation in mitochondrial membrane potential and increased leakage of cytochrome c, causing increased cleaved caspase-3 activity. There were significant alterations in phosphorylated AMP-activated protein kinase (p-AMPK), phosphorylated Unc-51 like kinase-1 (p-ULK1), PARKIN, PTEN-induced kinase 1 (PINK1), microtubule-associated protein 1 light chain 3 (LC3), and p62 proteins, which were more severely disrupted under the combined effect of IGF-IIRα overexpression plus DOX. Finally, LysoTracker Red staining showed that IGF-IIRα overexpression causes lysosomal impairment, which was rescued by rapamycin treatment. Taken together, we found that IGF-IIRα leads to mitochondrial oxidative stress, decreased antioxidant levels, disrupted mitochondrial membrane potential, and perturbed mitochondrial autophagy contributing to DOX-induced cardiomyopathy.

Chitosan oligosaccharides prevent doxorubicin-induced oxidative stress and cardiac apoptosis through activating p38 and JNK MAPK mediated Nrf2/ARE pathway

Doxorubicin (DOX) is one of the most effective chemotherapeutic drugs; however, the incidence of cardiotoxicity compromises its therapeutic index. Oxidative stress and apoptosis are believed to be involved in DOX-induced cardiotoxicity. Chitosan oligosaccharides (COS), the enzymatic hydrolysates of chitosan, have been reported to possess diverse biological activities including antioxidant and anti-apoptotic properties. The objective of the present study was to investigate the potential role of COS against DOX-induced cardiotoxicity, and the effects of COS on apoptosis and oxidative stress in rats and H9C2 cells. Furthermore, we also shed light on the involved pathways during the whole process. For this purpose, first, we demonstrated that COS exhibited a significant protective effect on cardiac tissue by not only inducing a decrease in body and heart growth but also ameliorated oxidative damage and ECG alterations in DOX-treated rats. Second, we found that COS reversed the decrease of cell viability induced by DOX, reduced the intracellular reactive oxygen species (ROS), increased the mitochondrial membrane potential (MMP) and Bcl-2/Bax ratio. COS treatment also results in reduced caspase-3 and caspase-9 expressions, and an increase in the phosphorylation of MAPKs (mitogen-activated protein kinases) in DOX-exposed H9C2 cells. Additionally, cellular homeostasis was re-established via stabilization of MAPK mediated nuclear factor erythroid 2-related factor 2/antioxidant-response element (Nrf2/ARE) signaling and transcription of downstream cytoprotective genes. In summary, these findings suggest that COS could be a potential candidate for the prevention and treatment of DOX-induced cardiotoxicity.

Increased myocardial 18F-FDG uptake as a marker of Doxorubicin-induced oxidative stress

BackgroundOxidative stress and its interference on myocardial metabolism play a major role in Doxorubicin (DXR) cardiotoxic cascade. MethodsMice models of neuroblastoma (NB) were treated with 5 mg DXR/kg, either free (Free-DXR) or encapsulated in untargeted (SL[DXR]) or in NB-targeting Stealth Liposomes (pep-SL[DXR] and TP-pep-SL[DXR]). Control mice received saline. FDG-PET was performed at baseline (PET1) and 7 days after therapy (PET2). At PET2 Troponin-I and NT-proBNP were assessed. Explanted hearts underwent biochemical, histological, and immunohistochemical analyses. Finally, FDG uptake and glucose consumption were simultaneously measured in cultured H9c2 in the presence/absence of Free-DXR (1 μM). ResultsFree-DXR significantly enhanced the myocardial oxidative stress. Myocardial-SUV remained relatively stable in controls and mice treated with liposomal formulations, while it significantly increased at PET2 with respect to baseline in Free-DXR. At this timepoint, myocardial-SUV was directly correlated with both myocardial redox stress and hexose-6-phosphate-dehydrogenase (H6PD) enzymatic activity, which selectively sustain cellular anti-oxidant mechanisms. Intriguingly, in vitro, Free-DXR selectively increased FDG extraction fraction without altering the corresponding value for glucose. ConclusionThe direct correlation between cardiac FDG uptake and oxidative stress indexes supports the potential role of FDG-PET as an early biomarker of DXR oxidative damage.

Aspalathin ameliorates doxorubicin-induced oxidative stress in H9c2 cardiomyoblasts

Aspalathin (ASP) is a C-dihydrochalcone abundantly found in Aspalathus linearis. While we have provide evidence that ASP can protect H9c2 cardiomyoblasts against doxorubicin (Dox)-induced apoptosis through regulation of autophagy, the complete mechanism involved in the cardioprotective effect of this dihydrochalcone remains to be explored. Here we provide evidence that ASP reverses Dox-induced apoptosis through the amelioration of oxidative stress in H9c2 cardiomyoblasts. Cultured cells were treated with 0.2 μM Dox or co-treated with either 20 μM dexrazoxane (Dexra) or 0.2 μM ASP daily for five days, to a final dose of 1 μM Dox, 100 μM Dexra and 1 μM ASP, respectively. Superoxide dismutase, catalase, glutathione, malondialdehyde and dichloro-dihydro-fluorescein diacetate fluorescence were used as end-point measurements for oxidative stress, while JC-1 and TUNEL labeling were performed to assess mitochondria depolarization and apoptosis. Co-treatment with ASP attenuated Dox-induced cardiotoxicity by improving endogenous antioxidant levels and mitochondrial membrane potential, while inhibiting reactive oxygen species production and cellular apoptosis. These findings suggested that ASP can prevent Dox-induced oxidative stress and apoptosis and needs further assessment to confirm its therapeutic potential to prevent Dox-induced cardiotoxicity.

Effects of Zataria multiflora Extract and Carvacrol on Doxorubicin-Induced Oxidative Stress in Rat Brain

Background: Due to the antioxidant effects of Zataria multiflora (ZM) and Carvacrol (CAR) in various problems and the prominent role of the ROS in neurotoxicity induced by Doxorubicin (DOX), this study was designed to investigate the effects of ZM hydroalcoholic extract and CAR on DOX-induced oxidative stress in rat brain Methods: 24 male rats were randomly divided into four groups including: 1)Control ,2)Doxorubicin (DOX) that received DOX via a tail vein on the first day of the study, 3,4) ZM+DOX and CAR+DOX which received ZM and CAR by gavage for 28 consecutive days. Brain tissue removed for redox markers evaluation. Results: MDA level in the DOX group was significantly increased compared to control group while in treated groups did not show any significant changes in comparison with the DOX group. Also, Thiol content in DOX group showed significant reduction compared to control group. Thiol contents in treated groups showed no significant difference compared to DOX group. Catalase (CAT) activity, an antioxidant enzyme, in the DOX group were significantly decreased compared to control group and increased in treated rats in comparison with the DOX group. Activity of Superoxide dismutase (SOD), an antioxidant enzyme, in the DOX group was significantly reduced compared to control group and increased in treated rats in comparison with the DOX group. Conclusion: The present study showed that ZM hydroalcoholic extract and CAR could inhibit DOX induced oxidative stress of the brain mainly with effect on the enzymatic antioxidant defense system.

12-Oxo-chenodeoxycholic acid potentiates doxorubicin-induced oxidative stress through Nrf2 axis in breast adenocarcinoma cells

12-Oxo-chenodeoxycholic acid potentiates doxorubicin-induced oxidative stress through Nrf2 axis in breast adenocarcinoma cells

Abstract 5815: Aldose reductase inhibition prevents doxorubicin-induced inflammatory response in endothelial cells and macrophages

Abstract Anthracycline class of chemotherapeutic drugs such as doxorubicin and daunorubicin has been known to be effective in the therapy of various types of cancer. However, in certain cancers such as colon cancer, the use of anthracyclines is restricted due to acquired drug resistance, which requires high amounts of drugs that cause severe toxic side effects. We have recently demonstrated that aldose reductase (AR) inhibitor, fidarestat, increases the sensitivity of doxorubicin towards colon cancer cells death in vitro and in vivo and decreases cardiotoxicity. However, the mechanisms through which AR inhibitor prevents doxorubicin-induced toxicity is not understood. We have examined how AR inhibition prevents doxorubicin-induced endothelial and cardiac toxicity along with inflammatory response in in vitro and in vivo models. Our results demonstrate that fidarestat prevents doxorubicin-induced oxidative stress, endothelial cell death, and monocyte adhesion. Further, fidarestat prevents the activation of NF-κB-dependent expression of endothelial cell markers ICAM-1 and VCAM-1 and expression of various inflammatory cytokines and chemokines in human vascular endothelial cells. In addition, fidarestat prevented the doxorubicin-induced decrease in eNOS and increase in iNOS expression. Similarly, AR inhibition prevented doxorubicin-induced endothelial dysfunction, cardiac hypertrophy, and cardiomyocyte injury in mice. Fidarestat also prevented doxorubicin-induced activation of monocytes and macrophages to proinflammatory phenotype in culture as well as in mouse models. Thus, our results suggest that by preventing doxorubicin-induced inflammatory as well as oxidative stress signals, fidarestat decreases cardiotoxic effects of doxorubicin. This is a novel adjuvant therapy of cancer using aldose reductase inhibitors with anthracyclines that would increase cancer therapeutic efficacy and decrease cardiotoxic side effects. Citation Format: Himangshu Sonowal, Ashish Saxena, Kota V. Ramana, Satish K. Srivastava. Aldose reductase inhibition prevents doxorubicin-induced inflammatory response in endothelial cells and macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5815.

Antioxidant activity of Spirulina platensis alleviates doxorubicin-induced oxidative stress and reprotoxicity in male rats

Male infertility is a common side effect of doxorubicin (DOX) that substantially impairs the quality of life of young cancer survivors. Therefore, the current work was designed to evaluate the possible antioxidant and gonado-protective effects of Spirulina platensis (S. platensis) in DOX-treated rats. Intraperitoneal administration of DOX (3 mg/kg b.wt.) once weekly for 5 weeks significantly decreased the levels of testicular catalase, superoxide dismutase and glutathione peroxidase. Moreover, it significantly decreased serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels, as well as sperm motility and sperm count. Additionally, DOX treatment significantly increased the testicular malondialdehyde concentration and the percent of sperm abnormalities and resulted in marked cystic dilation of seminiferous tubules with extensive separation, dissociation of germinal cells from the basement membrane and arrested spermatogenesis. Oral administration of S. platensis at a dose of 300 mg/kg daily for 5 weeks mitigated DOX-induced oxidative stress, testicular damage, hormone alterations and spermiogram abnormalities via its potent antioxidant activity. S. platensis may represent a potential therapeutic option to protect testicular tissue during DOX treatment.