Targeting Oxidative Stress, NLRP3 Inflammasome, and Autophagy by Fraxetin to Combat Doxorubicin-Induced Cardiotoxicity

Doxorubicin belongs to the class of anthracycline antibiotics that is widely used in the treatment protocols of a wide range of malignancies. The major deleterious effect of doxorubicin use is the possible occurrence of cardiotoxicity. This study aimed to delineate the possible effects of targeting oxidative stress, NLRP3 inflammasome, and autophagy by fraxetin on doxorubicin-induced cardiac dysfunction in rats. In a model of doxorubicin-induced cardiotoxicity, the effects of different doses of fraxetin were assessed by determination of biochemical, histopathological, immunohistochemical, and electron microscopic changes. Fraxetin, in a dose-dependent manner, was found to have the ability to mitigate the harmful effects of oxidative stress and inflammation on myocardial muscles with significant decrease in NLRP3 inflammasome, augmentation of autophagy, and amelioration of the apoptotic signaling pathways. In addition, fraxetin, in a dose-dependent manner, had the ability to combat the echocardiographic, histopathological, immunohistochemical, and electron microscopic changes induced by doxorubicin in cardiomyocytes. As a result, fraxetin may be put into consideration as a new adjuvant line of therapy on the way to mitigate doxorubicin-induced cardiotoxicity.

Enhanced Efficiency of the Removal of Cytostatic Anthracycline Drugs Using Immobilized Mycelium of Bjerkandera adusta CCBAS 930

The aim of this study was to evaluate the bioremoval of anthracycline antibiotics (daunomycin-DNR, doxorubicin–DOX, and mitoxantrone-MTX) by immobilized mycelium of B. adusta CCBAS 930. The activity of oxidoreductases: versatile peroxidases (VP), superoxide dismutase (SOD), catalase (CAT), and glucose oxidase (GOX), and the levels of phenolic compounds (PhC) and free radicals (SOR) were determined during the biotransformation of anthracyclines by B. adusta strain CCBAS 930. Moreover, the phytotoxicity (Lepidium sativum L.), biotoxicity (MARA assay), and genotoxicity of anthracyclines were evaluated after biological treatment. After 120 h, more than 90% of anthracyclines were removed by the immobilized mycelium of B. adusta CCBAS 930. The effective biotransformation of anthracyclines was correlated with detoxification and reduced genotoxicity.

Cardiotoxic Effects of Yew Tree and Pink Periwinkle Alkaloids

Antitumour herbal medicines based on pink periwinkle and yew tree alkaloids are included in combination therapies for many types of cancer. The use of these classes of products may entail cardiotoxic effects leading to life-threatening conditions. The aim of the study was to analyse scientific literature on cardiotoxic effects of anticancer drugs based on yew tree alkaloids (taxanes) and pink periwinkle alkaloids (vinca alkaloids). The results of the analysis demonstrated that the main manifestations of taxane-induced cardiotoxicity were bradycardia, atrioventricular block, atrial and ventricular arrhythmias. Concomitant use of taxanes and anthracycline antibiotics exacerbated cardiotoxic effects of both drug classes. The use of vinca alkaloids was associated with haematological toxicity in the form of neutropenia, while cardiotoxic effect was rarely observed during monotherapy. Raising awareness among oncologists, cardiologists, and other specialists involved in the management of cancer patients about potential cardiac complications of antitumour therapy contributes to early detection of adverse reactions and allows for individual correction of treatment regimens, especially in patients with predisposition to cardiovascular disease.

N-Alkylation of Anthracycline Antibiotics by Natural Sesquiterpene Lactones as a Way to Obtain Antitumor Agents with Reduced Side Effects

Anthracycline antitumor antibiotics are one of the promising classes of chemotherapeutic agents for cancer treatment. The main deterrent to their use is high toxicity to a healthy environment, including cumulative cardiotoxicity. In our work, bipharmacophore molecules containing in their structure a fragment of the known anthracycline antibiotics daunorubicin and doxorubicin and natural sesquiterpene lactones were obtained for the first time. When studying the biological activity of the synthesized compounds, it was found that with equal and, in some cases, higher cytotoxicity and glycolysis inhibition by anthracycline antibiotics conjugates with sesquiterpene lactones in comparison with doxo- and daunorubicin, a reduced damaging effect on the functioning of rat heart mitochondria was observed. The results obtained allow us to confirm the assumption that the chemical modification of the anthracycline antibiotics molecules doxo- and daunorubicin by natural sesquiterpene lactones can be a promising strategy for creating potential antitumor chemotherapeutic drugs with a pronounced cytotoxic effect on tumor cells and a reduced damaging effect on healthy cells of the human organism.

Antioxidant and Anti-Inflammatory Effects of Crocin Ameliorate Doxorubicin-Induced Nephrotoxicity in Rats

Doxorubicin is a drug that belongs to the anthracycline antibiotics. Nephrotoxicity is one of the serious side effects of doxorubicin treatment. Crocin, which is one of the most bioactive components of saffron, has antioxidant, anti-inflammatory, and antitumor effects. The current study was aimed at investigating the possible protective effects of crocin against doxorubicin-induced nephrotoxicity to elucidate the underlying mechanism of this effect. The study included four groups, six rats in each group: normal control, crocin control, doxorubicin, and crocin/doxorubicin. Doxorubicin and crocin/doxorubicin groups received intraperitoneal injections of doxorubicin (3.5 mg/kg twice weekly for 3 weeks). Rats in the crocin control group and the crocin/doxorubicin group were treated with intraperitoneal injections of crocin (100 mg/kg body weight per day) for 3 weeks. Biomarkers of kidney function and oxidative stress as well as the abundance of mRNA for nuclear factor-κβ and inducible nitric oxide synthase were evaluated. In addition, the abundance of cyclooxygenase 2 and tumor necrosis factor α immunoreactivity was evaluated. Crocin treatment had renoprotective effects manifested by significant improvement in kidney function as well as a reduction in the abundance of biomarkers of oxidative stress markers and inflammatory mediators. In conclusion, crocin has a protective effect against doxorubicin-induced nephrotoxicity in rats by serving as an antioxidant and attenuating the expression of NF-κB, iNOS, COX2, and TNFα.

Possibility to Biotransform Anthracyclines by Peroxidases Produced by Bjerkandera adusta CCBAS 930 with Reduction of Geno- and Cytotoxicity and Pro-Oxidative Activity

The aim of this study was to evaluate the bioremoval mechanism of anthracycline antibiotics by the white-rot fungus B. adusta CCBAS 930. The activity of oxidoreductases and levels of phenolic compounds and free radicals were determined during the biotransformation of anthraquinone antibiotics: daunomycin (DNR) and doxorubicin (DOX) by B. adusta strain CCBAS 930. Moreover, phytotoxicity (Lepidium sativum L.), ecotoxicity (Vibrio fischeri), genotoxicity and cytotoxicity of anthraquinone dyes were evaluated before and after biological treatment. More than 80% and 90% of DNR and DOX were removed by biodegradation (decolorization). Initial solutions of DNR and DOX were characterized by eco-, phyto-, geno- and cytotoxicity. Despite efficient decolorization, secondary metabolites, toxic to bacteria, formed during biotransformation of anthracycline antibiotics in B. adusta CCBAS 930 cultures. DNR and DOX metabolites did not increase reactive oxygen species (ROS) production in human fibroblasts and resazurin reduction. DNR metabolites did not change caspase-3 activity.

A Survey of Synthetic Routes and Antitumor Activities for Benzo[g]quinoxaline-5,10-diones

Anthracycline antibiotics play an important role in cancer chemotherapy. The need to improve their therapeutic index has stimulated an ongoing search for anthracycline analogs with enhanced properties. This review aims to summarize the common synthetic approaches to benzo[g]quinoxaline-5,10-diones and their uses in heterocyclic chemistry. Because of the valuable biological activities of the 1,4-diazaanthraquinone compounds, a summary of the most promising heterocyclic quinones is provided together with their antitumor properties.

Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow

Aim To study changes in markers for myocardial direct injury and dysfunction and endothelial dysfunction (ED) indexes in patients with indolent lymphoma during the antitumor treatment.Material and methods Current antitumor therapy for lymphoma is often associated with cardio- and vasculotoxicity, studying of which is a relevant scientific direction. Markers for myocardial direct injury and dysfunction and ED indexes were studied in patients with indolent lymphomas receiving polychemotherapy (PCT). The study included 77 patients with newly diagnosed indolent type lymphoma. The main group (n=52): mean age, 63.4±2.8 years, 15 (28.8 %) men who had received one course of PCT. The comparison group (n=25): mean age, 61.8±3.7 years, 8 (32 %) men who had not received PCT. Troponin I (TnI), high-sensitivity troponin I (hs-сTnI), heart-type fatty acid binding protein (h-FAВР), and N-terminal pro-B-type natriuretic peptide (NT-prоBNP) were measured in patients of both groups. ED was evaluated by measuring the level of vascular cell adhesion molecule (VCAM) and by assessing the structure and function condition of small blood vessels using photoplethysmography. In both groups, the study parameters were determined at the start of the study (T1) and following the PCT course in the main group; if the PCT schedule included anthracycline antibiotics, the second point (T2) was assessed at 6 h following the drug administration.Results In both groups, the level of NT-proBNP was increased. This increase was significantly more pronounced in the comparison group (49.896±23.228 vs 20.877±8.534 pmol/l, respectively, p=0.011) whereas a tendency to its increase was observed after the PCT course. Before the start of the treatment, laboratory and instrumental signs of ED were noticed: the level of VCAM was 4951±1297 and 3225±757 ng/ml in the comparison group and the main group, respectively (р=0.246); reflection index was <1.8 in 23 (44.2%) patients of the main group and in 16 (64%) patients of the comparison group (р=0.098). During the PTC course, the endothelial function significantly improved; the level of VCAM decreased by 748 ng/ml (p=0.016), which was associated with significant decreases in erythrocyte sedimentation rate by 2.71 mm/h (р=0.027) and lactate dehydrogenase level by 62.38 U/l (р=0.026). Statistically significant decreases in other inflammatory markers (alpha-2-globulin, fibrinogen, C-reactive protein, neutrophil count) were not observed.Conclusion The level of NT-proBNP showed the highest sensitivity in assessing the cardiotoxic effect of PCT. The dynamics of VCAM level suggested a possible role of the disease itself in the development of ED in this patient group.