Toxic Effects Of Doxorubicin Research Articles

The effects of propolis on doxorubicin-induced hepatorenal damage: a comparison of ethanolic and oily extracts of propolis

ABSTRACT The protective effect of ethanolic propolis extract (PE) in the toxic effects of doxorubicin (DOX), a chemotherapy drug, has been reported previously. Since ethanol usage has some restrictions, in the present study, olive oil as an alternative to ethanol has been tested in DOX-induced hepatorenal injury and the effectiveness of the two extracts were compared. Male rats were orally given PE or oily propolis extract (PO) for 15 days (50 mg/kg/day) and DOX was injected (15 mg/kg, intraperitoneally) on the 13th day. The animals were sacrificed and then hepatorenal oxidative stress and functional parameters were evaluated. DOX-induced reduction in hepatorenal functions and oxidative stress were significantly reduced in both propolis treatment groups. Treatment with PO was more effective in reducing DOX-induced oxidative stress, yet both extracts showed similar efficacy in improving hepatorenal functions. We suggest that the PO could be preferred to avoid the side effects of ethanol.

1,25(OH)2D3 ameliorates doxorubicin‑induced cardiomyopathy by inhibiting the NLRP3 inflammasome and oxidative stress.

Doxorubicin (DOX), as a chemotherapy agent with marked therapeutic effect, can be used to treat certain types of cancer such as leukemia, lymphoma and breast cancer. However, the toxic effects of DOX on cardiomyocytes limit its clinical application. Oxidative stress has been documented to serve a pivotal role in DOX-induced cardiomyopathy. Previous studies have reported that 1,25(OH)2D3 has antioxidant and anti-inflammatory effects and can inhibit the renin-angiotensin system. However, the effects of 1,25(OH)2D3 on the pathophysiological processes of DOX-induced cardiomyopathy and its mechanisms remain poorly understood. To investigate these potential effects, C57BL/6J mice were used to construct a DOX-induced cardiomyopathy model and treated with 1,25(OH)2D3. At 4 weeks after the first injection of DOX, cardiac function and myocardial injury were evaluated by echocardiograph and ELISA. Masson's trichrome staining and RT-qPCR were used to assess myocardial fibrosis, and immunohistochemistry and western blotting were performed to analyze expression levels of inflammation and oxidative stress, and the NLRP3 inflammasome pathway. ChIP assay was used to assess the effects of 1,25(OH)2D3 on histone modification in the NLRP3 and Nrf2 promoters. The results showed that 1,25(OH)2D3 treatment increased LVEF and LVFS, reduced serum levels of BNP and cTnT, inhibited the collagen deposition and profibrotic molecular expression, and downregulated the levels of inflammatory cytokines in DOX-induced cardiomyopathy. ROS and antioxidant indices were also ameliorated after 1,25(OH)2D3 treatment. In addition, 1,25(OH)2D3 was found to inhibit the NLRP3 inflammasome and KEAP-Nrf2 pathways through regulation of the levels of H3K4me3, H3K27me3 and H2AK119Ub in the NLRP3 and Nrf2 promoters. In conclusion, the present study demonstrated that 1,25(OH)2D3 regulated histone modification in the NLRP3 and Nrf2 promoters, which in turn inhibits the activation of NLRP3 inflammasome and oxidative stress in cardiomyocytes, alleviating DOX-induced cardiomyopathy. Therefore, 1,25(OH)2D3 may be a potential drug candidate for the treatment of DOX-induced cardiomyopathy.

Effect of selenium against doxorubicin-induced oxidative stress, inflammation, and apoptosis in the brain of rats: Role of TRPM2 channel

Doxorubicin (DOX) is widely used as an anticancer drug in humans' various solid and haematological tumours. Although many studies on the toxic effect of DOX are used in different organs, its impact on brain tissue has yet to be adequately studied. This study investigated the protective effect of selenium (Se) and the role of transient receptor potential melastatin‐2 (TRPM2) channel activation against brain damage caused by DOX administration. Sixty rats were randomly divided into the sham, dimethyl sulfoxide (DMSO), DOX, DOX + Se, DOX + N-(p-amylcinnamoyl) anthranilic acid (ACA), and DOX + Se + ACA groups. The reactive oxygen species (ROS), poly [ADP-ribose] polymerase 1 (PARP1), and TRPM2 channel levels in brain tissues were measured by ELISA. In addition, a histopathological examination was performed in the cerebral cortex and hippocampal areas, and the TRPM2 channel, NF-κB, and caspase-3 expression were determined immunohistochemically. The levels of ROS, PARP1 and TRPM2 channel in the DOX group were higher than in the sham and DMSO groups (P < 0.05). However, these parameters were decreased in the in DOX+Se and DOX+ACA groups by the treatments of Se and ACA (P < 0.05). Also, we determined that Se and ACA treatment decreased the NF-κB, caspase-3, and TRPM2 channel expression in the cerebral cortex and hippocampal areas in the DOX-induced rats. The data showed that Se and/or ACA administration together with DOX administration could be used as a protective agent against DOX-induced brain damage.

Study of the laser radiation effect in combination with doxorubicin on the survival of MCF7 and MCF7DOX culture cells

The use of lasers in oncology is constantly evolving. In recent years, the mechanisms of the effect of laser radiation, particularly of the infrared spectrum, on tumour cells in combination with various chemotherapeutic agents have been studied.
 The aim. To study the effect of laser radiation with a wavelength of 660 and 810 nm on the survival of tumour cell cultures MCF7 and MCF7DOX in the presence of doxorubicin.
 Materials and methods. Tumour cells of MCF7 and MCF7DOX cultures were cultured in DMEM medium (Biowest, France) with 10 % fetal calf serum (FST) (Biowest, France) and 40 μg / ml gentamicin (Sigma, USA). Doxorubicin was added to the cells to a final concentration of 1 μg / ml. Cells were irradiated with a laser (Photonica-Plus, Ukraine) with a wavelength of 660 and 810 nm (irradiation time – 5 min, power density – 50 mV/cm2, irradiation dose 15 J/cm2). The results were recorded using a multiwell spectrophotometer (Labsystems Multiskan PLUS, Finland). Photomicrographs of cells were taken using a Carl Zeiss microscope, Germany.
 Results. Cell survival assessment and morphological characteristics in micropreparations indicate the antitumor efficacy of the combined effects of laser irradiation and doxorubicin. The most pronounced cytotoxic effect on MCF7-DOX culture cells was caused by doxorubicin exposure for 90 min in combination with infrared laser irradiation (λ=810 nm).
 Conclusions. Infrared laser light synergises with the toxic effects of doxorubicin and creates favourable conditions for apoptosis of tumour cells, as evidenced by cytomorphological data.

Kardiotoksičnost doksorubicina - uzroci, dijagnostika, posledice i mogućnosti prevencije

Introduction: Doxorubicin is an antibiotic from the anthracycline group, with clinical use limited by adverse reactions, primarily cardiotoxicity. Material and Methods: This article provides an overview of therapeutic and toxic doses of doxorubicin, the mechanism of side effects, markers for early detection as well as currently available preparations for preventing its toxicity. We searched PubMed, Google Scholar, SCIndex, Dimension, Scopus and Google for English and Serbian language abstracts, using the searching terms "doxorubicin", "cardiotoxicty", "carotenoids", "oncology", "oxidative stress", "DNA damage" and "biomarkers". Topic: The mechanism of side effects is still unclear and is considered to be multifactorial including ROS overproduction, reducing levels of endogenous antioxidants, DNA damage, large drug accumulation in cardiac tissue, calcium overload, histamine release, and impairment of autoimmune regulation of cardiac function Manifestations of cardiotoxicity are mainly acute (appear inside 24h atypical changes of ST segment, decrease in QRS complex voltage, tachycardia and supraventricular extrasystoles are observed, but can also be subacute and chronic (cardiomyocyte edema, disorganzation, fibroblast proliferation, necrosis). Diagnosis of cardiotoxicity is based on ECG, ECHO, and biochemical markers, among which the most important are troponins, while pathohistological verification is necessary for the final diagnosis. Some medications (carvedilol, atorvastatin) have showed some level of cardioprotection against DOX, but there is no overall agreement on their administration solely for this purpose. An increasing number of studies have tested various dietary supplements and natural preparations (already in the human diet) in order to discover those that could completely prevent or reduce the toxic effects of doxorubicin, with special focus on carotenoids. Conclusion: Cardiotoxicity is the leading side effect of doxorubicin, and therefore there is an active search for either new biomarkers and/or diagnostic protocols that would detect toxicity in time, as well as substances able to prevent the occurrence or alleviate DOXinduced cardiotoxicity.

In Vivo and In Vitro Protective Effects of Rosmarinic Acid against Doxorubicin-Induced Cardiotoxicity

Doxorubicin (DOX) is an anticancer medicine that may trigger cardiomyopathy. Rosmarinic acid (RA) has shown antioxidant, anti-inflammatory, and anticancer effects. This investigation assessed the cardioprotective effect of RA on DOX-induced-toxicity in both in vivo and in vitro experiments. Male rats were randomized on 7 groups: (1) control, (2) DOX (2 mg/kg, per 48 h, 12d, i.p), (3) RA (40 mg/kg, 12d, i.p.), (4–6) RA (10, 20, 40 mg/kg, 16d, i.p.)+ DOX, (7) Vitamin E (200 mg/kg, per 48 h, 16d, i.p.) + DOX and then indices of cardiac function were estimated. Also, DOX and rosmarinic acid effects were examined on MCF7 cells (breast cancer cells line) to clarify that both cardiotoxicity and anticancer effects were analyzed. DOX increased heart to body weight ratio, RRI, QA, STI, QRS duration and voltage, attenuated HR, blood pressure, Max dP/dt, Min dP/dt, LVDP, enhanced MDA, declined GSH amount, and caused fibrosis and necrosis in cardiac tissue. Administration of RA ameliorated the toxic effects of DOX. In vitro studies showed that RA did not affect the cytotoxic effect of DOX. RA as an antioxidant, anti-inflammatory, and cardioprotective compound could be a promising compound to help minimize DOX-induced cardiotoxicity.

The effect of glucose on doxorubicin and human hemoglobin interaction: Characterization with spectroscopic techniques

The application of doxorubicin (DOX), which is the most effective anticancer drug, is limited due to its cardiac toxicity. The study of DOX-hemoglobin (Hb) interaction has biochemical and toxicological importance. Understanding the Hb-DOX interaction in the presence of glucose (Glc), as the main blood sugar, can be advantageous for clinical implications. In this study, the structural changes imposed by DOX on Hb in the presence of various concentrations of Glc were investigated using different methods such as UV–Vis, fluorescence, and circular dichroism (CD) spectroscopy. The results obtained by the spectroscopic techniques revealed that the hyperchromic effect, which was observed after treating Hb with DOX, was relieved in the presence of Glc. Based on the results of fluorescence spectroscopy, some of the photons emitted from the tryptophan (Trp) residues were quenched due to DOX binding. Since the Trp residues were exposed, the intrinsic fluorescence of Hb increased but the residues might not have been competent for DOX binding anymore. The results of the CD technique demonstrated that the levels of the alpha-helix structure were significantly reduced when Hb was simultaneously treated with DOX and Glc. Thermal stability studies revealed that the melting temperature of Hb increased in the presence of Glc alone. However, the thermal stability of Hb decreased in the presence of Glc/DOX (combined). Since the concentration of Glc in diabetic patients is significantly higher than in healthy individuals, the toxic effects of DOX, due to its interaction with Hb, may be different in healthy and diabetic subjects.

THE PROPHYLACTIC APPROACH OF SESAMOL AND 3′,4′-(METHYLENEDIOXY)ACETOPHENONE TO PREVENT ASSOCIATED CARDIOTOXICITY OF DOXORUBICIN AT HIGH DOSE IN PROSTATE CANCER RAT MODEL

The clinical application of Doxorubicin (DOX) is restricted due to the incidence of myelotoxicity and cardiotoxicity. Damages caused by free radicles to cardiac muscle tissues are more and permanent. The potent ROS scavenger, Sesamol (SM) has been proven to be effective in diseases related to oxidative stress. Thus, SM can be a good choice for myocardial protection against oxidative stress. 3′,4′-(Methylenedioxy) acetophenone (3’MA) being derivative of SM have been proven in our lab to be antioxidant. Thus, both SM and 3’MA may be having ROS scavenging potential. In this study, we have examined the efficacy of SM and 3’MA protection against toxic effects of DOX at high dose administration in prostate cancer (PCa) induced rats. Results from the study indicate that doxorubicin (4mg/kg) was potent to shows the anticancer activity in prostate cancer but also induce myocardial damage. The histopathological evaluation, Serum creatine kinase-muscle/brain (CK-MB) estimation, heart weight and tibia length ratio and haematology data suggest that the toxicity induced by DOX was prevented by SM and 3’MA treatment. Hence, the hypothesis proposed for this study and data generated from this study shows that SM and 3’MA can be drugs to augment the toxicity of DOX.

Evaluation of the effect of the combination of glucosamine derivatives with quercetin on the morphofunctional state of the thymus and spleen of rats under the toxic effect of doxorubicin

In the rating of the most used antineoplastic drugs, the antibiotic of the anthracycline series doxorubicin occupies a significant place. The introduction of doxorubicin into clinical practice has made it possible to improve the current and delayed results of treatment; however, the non-selective spectrum of its cytostatic action is manifested by a number of drug-dependent side effects, among them cardio- and myelotoxicities are the most characteristic ones. Among the modern and proven approaches to the pharmacocorrection of the organotoxic effect of doxorubicin, it is considered traditional to carry out the supporting therapy using drugs of various pharmacotherapeutic groups, which action is directed to the corresponding affected organ/target system. A significant disadvantage of this approach is the creation of prerequisites for polypharmacy and, consequently, all the negative consequences of its use. Currently, scientific data on the prospects of searching for products of the supporting therapy among biologically active substances of natural origin and their combinations characterized by a universal multicomponent mechanism of the cytocorrective action, pronounced therapeutic effectiveness and a high safety profile continue to appear.Aim. To study the combination of glucosamine derivatives with quercetin as a potential сorrector of the immunotoxic action of doxorubicin in the experiment in rats.Materials and methods. The study in evaluating the corrective effect of the combination of glucosamine derivatives with quercetin under conditions of doxorubicin intoxication was performed on 75 rats. To simulate intoxication, experimental animals (excluding the intact group) were injected intraperitoneally with doxorubicin in the dose of 5 mg/kg of the body weight once a week for four weeks. The combination under research was administered once daily intragastrically for 28 days after the first injection of the cytostatic. The histomorphological studies of the thymus and spleen were performed using standard methods of light microscopy.Results. In the course of the study, it was shown that under the effect of the combination of glucosamine derivatives with quercetin studied a decrease in dystrophic changes in the thymus and spleen of rats was observed, the intensity of regeneration processes increased, indicating the restoration of the functional state of immunocompetent organs. By the severity of the protective effect the combination studied was superior to monocomponent reference samples of glucosamine hydrochloride and quercetin.Conclusions. The combination of glucosamine derivatives with quercetin has a corrective effect on the state of the organs of immunogenesis (thymus and spleen) under conditions of the development of doxorubicin intoxication in rats and is a promising subject for further pharmacological study as a modifier of the immunosuppressive effect of doxorubicin.

Co-administration of imipramine and doxorubicin reduces the survival rate and body weight of mice.

Doxorubicin (DOX) is a chemotherapeutic agent widely used to treat cancers, particularly breast cancer. DOX has side effects, including cardiotoxicity, hepatotoxicity, and nephrotoxicity. Imipramine is an antidepressant that increases the release of neurotransmitters. This study aimed to investigate the effect of co-administration of imipramine and DOX on DOX-induced toxicity. Forty female mice (10-12-weeks-old, 30-38 g) were divided into four groups (n = 10 per group). The animals in the control group received a single-dose saline injection. The animals in the DOX group received a single dose of DOX (20 mg/kg) by intraperitoneal (i.p.) injection. The animals in the imipramine group received the drug daily in their drinking water (0.13 mg/mL) for 9 days, starting 1 day before the DOX injection received by the DOX group. The animals in the combination group (DOX+imipramine) received a single dose of DOX (20 mg/kg, i.p. injection), and a daily dose of imipramine in their drinking water (0.13 mg/mL) for 9 days starting 1 day before the DOX injection. The animals were observed daily to record mortality, and their body weights were recorded every alternate day. DOX treatment increased the rate of mortality compared with that for control animals. Imipramine co-administration with DOX increased the rate of mortality significantly (p < 0.05) compared with DOX treatment alone. The mortality rate in both the control and imipramine-treatment groups was zero. DOX co-administered with imipramine resulted in significantly reduced body weight compared with control animals. The combination of DOX and imipramine reduced the survival rate of female mice, suggesting that imipramine increases the toxic effects of DOX.

A sulfur dioxide polymer prodrug showing combined effect with doxorubicin in combating subcutaneous and metastatic melanoma

Melanoma, as the most aggressive and treatment-resistant skin malignancy, is responsible for about 80% of all skin cancer mortalities. Prone to invade into the dermis and form distant metastases significantly reduce the patient survival rate. Therefore, early treatment of the melanoma in situ or timely blocking the deterioration of metastases is critical. In this study, a sulfur dioxide (SO2) polymer prodrug was designed as both an intracellular glutathione (GSH)-responsive SO2 generator and a carrier of doxorubicin (DOX), and used for the treatment of subcutaneous and metastatic melanoma. Firstly, chemical conjugation of 4-N-(2,4-dinitrobenzenesulfonyl)-imino-1-butyric acid (DIBA) onto the side chains of methoxy poly (ethylene glycol) grafted dextran (mPEG-g-Dex) resulted in the synthesis of the amphiphilic polymer prodrug of SO2, mPEG-g-Dex (DIBA). The obtained mPEG-g-Dex (DIBA) could self-assemble into stable micellar nanoparticles and exhibited a glutathione-responsive SO2 release behavior. Subsequently, DOX was encapsulated into the core of mPEG-g-Dex (DIBA) micelles to form DOX-loaded nanoparticles (PDDN-DOX). The formed PDDN-DOX could be internalized by B16F10 cells and synchronously release DOX and SO2 into the tumor cells. As a result, PDDN-DOX exerted synergistic anti-tumor effects in B16F10 melanoma cells because of the oxidative damage properties of SO2 and toxic effects of DOX. Furthermore, in vivo experiments verified that PDDN-DOX had great potential for the treatment of subcutaneous and metastasis melanoma. Collectively, our present work demonstrates that the combination of SO2-based gas therapy and chemotherapeutics offers a new avenue for inhibiting melanoma progression and metastases.

Intermittent Fasting Attenuates Apoptosis, Modulates Autophagy and Preserve Telocytes in Doxorubicin Induced Cardiotoxicity in Albino Rats: A Histological Study

Background: Doxorubicin (DOX) is an effective anticancer drug, however its use is limited due to severe cardiotoxic effects as ventricular dysfunction, cardiomyopathy and heart failure. Intermittent fasting (IF) has a potential preventive and therapeutic effects against variety of diseases including cardiovascular and neurodegenerative disorders.Aim of Work: Investigating the effects of DOX on the histological structure of myocardium and evaluating the possible cardioprotective effects of IF on these changes.Materials and Methods: Forty eight adult male albino rats were divided equally into four groups: control, fasting (16 hours fasting /8 hours eating), DOX (received 3 mg/kg every other day for a total of six intraperitoneal injections) and fasting DOX. Body weight, levels of cardiac biomarkers, Malondialdehyde (MDA) and autophagic indicators (LC3II & p62) were measured. Myocardial specimens were processed for paraffin blocks and stained with H&E, Mallory’s trichrome and immunohistochemical stains for p53. Moreover, resin blocks were processed for semithin and ultrathin sections examination. Morphometric and statistical studies were performed.Results: In DOX group, cardiac biomarkers, MDA, LC3II and p62 levels were significantly elevated compared to control group. In addition to, marked histological alterations in myocytes, telocytes and autophagic process. Also, there was significant decrease in cardiomyocytes diameter, significant increase in p53 positive cells and area percent of collagen fibres versus control. On the other hand, IF protected cardiac tissues against the toxic effects of DOX as evidenced by amelioration of histopathological changes and the non significant difference in the levels of cardiac enzymes, MDA, LC3II and p62, cardiomyocytes diameter, p53 positive expressions and area percent of collagen fibres compared to control group.Conclusion: Doxorubicin administration resulted into deleterious effects on the myocardium. Intermittent fasting had cardioprotective effects against Dox-induced cardiotoxicity via restoration of oxidative state, attenuation of apoptosis, regulation of autophagic process and preservation of telocytes.

Curcumin loaded mesoporous silica nanoparticles: assessment of bioavailability and cardioprotective effect

Rhizomes of the plant Curcuma longa has been traditionally used in medicine and culinary practices in India. It possesses various pharmacological effect, namely, antioxidant, hepatoprotective, anti-inflammatory, anti-thrombosis, and anti-apoptotic. The study was undertaken to assess the effect of curcumin and curcumin loaded mesoporous silica nanoparticles (MSNs) against doxorubicin (DOX)-induced myocardial toxicity in rats. Furthermore, the study also included the bioavailability estimation of curcumin delivered alone and delivered via mesoporous technology. Cardiotoxicity was produced by cumulative administration of DOX (2.5 mg/kg for two weeks). Curcumin and curcumin loaded mesoporous nanoparticles (MSNs) each 200 mg/kg, po was administered as pretreatment for two weeks and then for two alternate weeks with DOX. The repeated administration of DOX induced cardiomyopathy associated with an antioxidant deficit and increased level of cardiotoxic biomarkers. Pretreatment with curcumin (alone and via MSNs) significantly protected myocardium from the toxic effects of DOX by significantly decreased the elevated level of malondialdehyde and increased the reduced level of reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in cardiac tissue. MSNs based delivery was found superior compared to curcumin delivered alone. Moreover, the results of bioavailability assessment in rats clearly indicated higher Cmax and AUC values in rats when curcumin was administered via MSNs indicating superior bioavailability. The bioavailability of curcumin loaded MSNs, biochemical and histopathology reports support the good cardioprotective effect of curcumin which could be attributed to its increased bioavaibility lead to good antioxidant and anti-inflammatory activity.

Cardioprotective effect of vitamin D and melatonin on doxorubicin-induced cardiotoxicity in rat model: an electrocardiographic, scintigraphic and biochemical study

Objectives: Doxorubicin (DOX) is an antineoplastic drug that is widely used in chemotherapy but its cardiotoxicity is the most important side effect that limits the clinical use of this drug. We investigated DOX treatment and the effects of vitamin D and melatonin on heart by electrocardiography, scintigraphic and biochemical methods. Methods: In this study, forty-nine adult male Wistar albino rats (220 ± 15 g) were randomly divided into seven groups (n = 7 each), namely control (CON, n = 7), doxorubicin (DOX, n = 7), melatonin (MEL, n = 7), vitamin D (Vit D, n = 7), doxorubicin plus melatonin (DOX+MEL, n = 7), doxorubicin plus vitamin D (DOX+Vit D, n = 7), and doxorubicin plus melatonin and vitamin D (DOX+MEL+Vit D, n = 7) groups. Cardiotoxicity was induced by intraperitoneal injection (i.p.) of DOX (18 mg/kg, i.p.) on the 15th, 16th and 17th days. Rats receiving vitamin D and melatonin treatment in the DOX-induced cardiotoxicity group received vitamin D (60,000 IU/kg, i.p.) were administered in a single dose and melatonin (40 mg/kg/day, i.p.) for 17 days and were injected with (18 mg/kg, i.p.) on doxorubicin 15th, 16th, and 17th days. On the 18th day electrocardiography (ECG), 99mTechnetium pyrophosphate scintigraphy and biochemical parameters were assessed. Results: DOX caused changes in the ECG pattern, a significant decrease in heartbeat (p &amp;lt; 0.01), P wave (p &amp;lt; 0.001) and QRS complex durations (p &amp;lt; 0.001), R wave amplitude (p &amp;lt; 0.001); elevation in ST-segment (p &amp;lt; 0.001) and decrease in QT interval (p &amp;lt; 0,001), and R-R interval durations (p &amp;lt; 0.001); increase in the serum levels of cardiac injury markers (CK, BUN, cardiac troponin T), (p &amp;lt; 0.01), and increased 99mTechnetium pyrophosphate uptake (p &amp;lt; 0.001) as compared to the CON group. MEL, Vit D and MEL+Vit D administration showed a same protective effect against DOX-induced altered ECG pattern. Pre-treatment with MEL, Vit D and MEL+Vit D significantly protected the heart from the toxic effect of DOX, by decreasing the levels of of cardiac injury markers (CK, BUN, cardiac troponin T) (p &amp;lt; 0.001) and decreased the elevated level of 99mTechnetium pyrophosphate uptake (p &amp;lt; 0.001). Conclusion: Vitamin D and melatonin treatment prevented all the parameters of DOX-induced cardiotoxicity in rats.

Apigenin and hesperidin augment the toxic effect of doxorubicin against HepG2 cells

BackgroundHepatocellular carcinoma (HCC) is one of the most common malignancies, with an increasing incidence. Despite the fact that systematic chemotherapy with a doxorubicin provides only marginal improvements in survival of the HCC patients, the doxorubicin is being used in transarterial therapies or combined with the target drug – sorafenib. The aim of the study was to evaluate the effect of natural flavonoids on the cytotoxicity of the doxorubicin against human hepatocellular carcinoma cell line HepG2.MethodsThe effect of apigenin and its glycosides - cosmosiin, rhoifolin; baicalein and its glycosides – baicalin as well as hesperetin and its glycosides – hesperidin on glycolytic genes expression of HepG2 cell line, morphology and cells’ viability at the presence of doxorubicin have been tested. In an attempt to elucidate the mechanism of observed results, the fluorogenic probe for reactive oxygen species (ROS), the DNA oxidative damage, the lipid peroxidation and the double strand breaks were evaluated. To assess impact on the glycolysis pathway, the mRNA expression for a hexokinase 2 (HK2) and a lactate dehydrogenase A (LDHA) enzymes were measured. The results were analysed statistically with the one-way analysis of variance (ANOVA) and post hoc multiple comparisons.ResultsThe apigenin and the hesperidin revealed the strongest effect on the toxicity of doxorubicin. Both flavonoids simultaneously changed the expression of the glycolytic pathway genes - HK2 and LDHA, which play a key role in the Warburg effect. Although separate treatment with doxorubicin, apigenin and hesperidin led to a significant oxidative DNA damage and double strand breaks, simultaneous administration of doxorubicin and apigenin or hesperidin abolished these damage with the simultaneous increase in the doxorubicin toxicity.ConclusionThe obtained results indicate the existence of a very effective cytotoxic mechanism in the HepG2 cells of the combined effect of doxorubicin and apigenin (or hesperidin), not related to the oxidative stress. To explain this synergy mechanism, further research is needed, The observed intensification of the cytotoxic effect of doxorubicin by this flavonoids may be a promising direction of the research on the therapy of hepatocellular carcinoma, especially in a chemoembolization.

New Cell-Penetrating Peptide (KRP) with Multiple Physicochemical Properties Endows Doxorubicin with Tumor Targeting and Improves Its Therapeutic Index

Cell-penetrating peptides (CPPs) are considered as promising drug carriers by virtue of their potent cell-penetrating capacity. However, lack of targetability still represents a bottleneck for their systemic administration. Here, we synthesized a lysine-rich CPP named KRP and developed a tumor-targeted drug delivery system (DDS) by linking KRP and doxorubicin (DOX) with stable covalent bonds (thioether bond and amide bond). Through in vitro and in vivo tests, we confirmed that the multiple physicochemical properties of KRP endow KRP-DOX with multiple synergistic functions, including good biocompatibility and biodistribution, selective accumulation in tumor tissues, inclination to remain in tumor tissues and be internalized by tumor cells; stable covalent bonds prevent free DOX release from KRP-DOX in blood stream, shield normal tissues from the toxic effect of DOX, and lead to the majority of DOX delivery into tumor cells by KRP; lysosome escape of KRP-DOX ensures its tumor-killing effect. In addition, the simple chemical composition and modification reduce the risk of immunogenicity and metabolite toxicity. Our study provides a simple, safe, and efficient platform for tumor-targeted DDS.

Cardioprotective effect of oregano oil against doxorubicin-induced myocardial infarction in rats

Aim: The objective of the study was to evaluate the cardioprotective effect of oregano oil (O.OIL) in doxorubicin (DOX)-induced myocardial infarction (MI) in rats. Materials and Methods: O.OIL (100 mg/kg and 200 mg/kg, p.o) was administered for 21 days in rats. MI was induced by DOX (5 mg/kg, i.p.) administered on the 7th, 14th, and 21st day of the study to obtain a cumulative dose of 15 mg/kg. On day 22, changes in electrocardiogram (ECG); force of contraction; serum markers: lactate dehydrogenase (LDH), creatine kinase (CK) MB isoenzyme, troponin I; lipid profile: total cholesterol and triglycerides; antioxidant enzymes level: malondialdehyde (MDA) and glutathione (GSH); heart and body weight; and histopathology of heart were determined. Results: Pretreatment with O.OIL significantly protected the myocardium from the toxic effects of DOX by reducing the elevated level of CK-MB, LDH, and troponin I to the normal levels. O.OIL increased the GSH levels and decreased the MDA levels in cardiac tissue. It also restored the changes in ECG and force of contraction and showed significant recovery of heart tissue in histopathological studies. Statistical analysis: All results are expressed as mean ± standard error of the mean. The results were analyzed for statistical significance by one-way ANOVA followed by Dunnet's Multiple Comparison Test using GraphPad version 5.01, P Abbreviations used: ECG: Electrocardiogram; O.OIL: Oregano oil; DOX: Doxorubicin; MI: Myocardial infarction.

Acacia hydaspica R. Parker prevents doxorubicin-induced cardiac injury by attenuation of oxidative stress and structural Cardiomyocyte alterations in rats

BackgroundThe use of doxorubicin (DOX) an anthracycline antineoplastic agent is withdrawn due to its cardio-toxic side effects. Oxidative stress has been recognized as the primary cause of DOX induced cardiotoxicity. We have investigated whether polyphenol rich ethyl acetate extract of Acacia hydaspica (AHE) can attenuate doxorubicin-induced cardiotoxicity via inhibition of oxidative stress.MethodsAHE was administered orally to rats once daily for 6 weeks at doses of 200 and 400 mg/kg b.w. DOX (3 mg/kg b.w. i.p., single dose/week) was administered for 6 weeks (chronic model). The parameters studied to evaluate cardioprotective potential were the serum cardiac function biomarkers (CK, CKMB, AST and LDH), hematological parameters, cardiac tissue antioxidant enzymatic status and oxidative stress markers, and histopathological analysis to validate biochemical findings.ResultsChronic 6 week treatment of DOX significantly deteriorated cardiac function biomarkers and decreased the activities of antioxidant enzymes, whereas significant increase in oxidative stress biomarkers was noticed in comparison to control group. AHE dose dependently protected DOX-induced leakage of cardiac enzymes in serum and ameliorated DOX-induced oxidative stress; as evidenced by decreasing lipid peroxidation, H2O2 and NO content with increase in phase I and phase II antioxidant enzymes. Doxorubicin treatment produced severe morphological lesions, leucopenia, decrease in red blood cell counts and hemoglobin concentrations. AHE co-treatment protected the heart and blood elements from the toxic effects of doxorubicin as indicated by the recovery of hematological parameters to normal values and prevention of myocardial injuries in a dose dependent way. The protective potency of AHE (400 mg/kg b.w) was equivalent to silymarin.ConclusionResults revealed that AHE showed protective effects against DOX induce cardiotoxicity. The protective effect might attribute to its polyphenolic constituents and antioxidant properties. AHE might be helpful in combination therapies as safer and efficient.

AKAP-Lbc mediates protection against doxorubicin-induced cardiomyocyte toxicity

Doxorubicin (DOX) is a chemotherapic agent that is widely used to treat hematological and solid tumors. Despite its efficacy, DOX displays significant cardiac toxicity associated with cardiomyocytes death and heart failure. Cardiac toxicity is mainly associated with the ability of DOX to alter mitochondrial function. The current lack of treatments to efficiently prevent DOX cardiotoxicity underscores the need of new therapeutic approaches. Our current findings show that stimulation of cardiomyocytes with the α1-adrenergic receptor (AR) agonist phenylephrine (PE) significantly inhibits the apoptotic effect of DOX. Importantly, our results indicate that AKAP-Lbc is critical for transducing protective signals downstream of α1-ARs. In particular, we could show that suppression of AKAP-Lbc expression by infecting primary cultures of ventricular myocytes with lentiviruses encoding AKAP-Lbc specific short hairpin (sh) RNAs strongly impairs the ability of PE to reduce DOX-induced apoptosis. AKAP-Lbc-mediated cardiomyocyte protection requires the activation of anchored protein kinase D1 (PKD1)-dependent prosurvival pathways that promote the expression of the anti-apoptotic protein Bcl2 and inhibit the translocation of the pro-apoptotic protein Bax to mitochondria. In conclusion, AKAP-Lbc emerges as a coordinator of signals that protect cardiomyocytes against the toxic effects of DOX.

Response of cultured normal canine mammary epithelial cells to deracoxib-doxorubicin combination.

Currently, there is a growing interest in combining anticancer drugs with the aim to improve outcome in patients suffering from tumours and reduce the long-term toxicity associated with the current standard of treatment. In this study, we evaluated the possible role of deracoxib against the toxicity of doxorubicin on normal canine mammary epithelial cells. The effect of deracoxib and doxorubicin combination on cell viability was determined by MTT assay. Apoptosis was characterised by flow cytometry. Cell nitrite concentrations were measured with the Griess reaction. Deracoxib (50 and 100 μM) treatment decreased the cytotoxic action of doxorubicin at 0.9 μM in the cells, from 33.63% to 13.4% and 25.82%, respectively. Our results also showed that the reverse effect of deracoxib on doxorubicin-induced cytotoxic activity in the cells was associated with a marked (3.04- to 3.57-fold) decrease in apoptosis. In additional studies identifying the mechanism of the observed effect, deracoxib exhibited an activity to prevent doxorubicin-mediated overproduction of nitric oxide in the cells. Our in vitro study results indicate that deracoxib (50 and 100 μM) can be beneficial in protecting normal cells from the toxic effect of doxorubicin in conjunction with apoptosis by the modulation of nitric oxide production.