Anthracyclines, e.g., doxorubicin (DOX), and anthracenediones, e.g., mitoxantrone (MTX), are drugs used in the chemotherapy of several cancer types, including solid and non-solid malignancies such as breast cancer, leukemia, lymphomas, and sarcomas. Although they are effective in tumor therapy, treatment with these two drugs may lead to side effects such as arrhythmia and heart failure. At the same clinically equivalent dose, MTX causes slightly reduced cardiotoxicity compared with DOX. These drugs interact with iron to generate reactive oxygen species (ROS), target topoisomerase 2 (Top2), and impair mitochondria. These are some of the mechanisms through which these drugs induce late cardiomyopathy. In this review, we compare the cardiotoxicities of these two chemotherapeutic drugs, DOX and MTX. As described here, even though they share similarities in their modes of toxicant action, DOX and MTX seem to differ in a key aspect. DOX is a more redox-interfering drug, while MTX induces energy imbalance. In addition, DOX toxicity can be explained by underlying mechanisms that include targeting of Top2 beta, mitochondrial impairment, and increases in ROS generation. These modes of action have not yet been demonstrated for MTX, and this knowledge gap needs to be filled.

BackgroundThe 3β, 6β, 16β-trihydroxylup-20(29)-ene (TTHL) is a pentacyclic triterpene obtained from the medicinal plant Combretum leprosum Mart. In folk medicine, this plant is popularly known as mofumbo, cipoaba or mufumbo, and is used to treat several diseases associated with inflammation and pain.MethodsWe investigated the antitumor efficacy of TTHL isolated from C. leprosum. The TTHL cytotoxic effect was investigated in MRC5, MCF-7, HepG2, T24, HCT116, HT29, and CACO-2 cells after 24, 48, 72 and 120 h of treatment. The mechanisms of cell death and DNA damage induction were investigated by flow cytometry and comet assay, respectively.ResultsThe results indicated that TTHL induced a time- and concentration-dependent growth inhibition in all human cancer cell lines. The cytotoxicity was more pronounced in MCF-7 breast cancer cells, with an IC50 of 0.30 μg/mL at 120 h. We therefore evaluated the cell death mechanism induced by TTHL (IC20, IC50, and IC80) in MCF-7 cells at 24 h. We found that the treatment with IC50 and IC80 TTHL for 24 h induced apoptosis in 14% (IC50) and 52% (IC80) of MCF-7 cells. The apoptosis induced by TTHL was accompanied by increased levels of both cleaved caspase-9 and intracellular ROS. In order to further understand the biological mechanism of TTHL-induced cytotoxicity, we have also investigated its effect on different Saccharomyces cerevisiae yeast strains. The mutant strains sod1Δ, sod2Δ, and sod1Δsod2Δ, which are deficient in superoxide dismutase antioxidant defenses, were hypersensitive to TTHL, suggesting that its capacity to disturb cellular redox balance plays a role in drug toxicity. Moreover, TTHL induced mutagenicity in the yeast strain XV185-14c.ConclusionsTaken together, the results suggest that TTHL forms covalent adducts with cellular macromolecules, potentially disrupting cellular function and triggering apoptosis.Electronic supplementary materialThe online version of this article (doi:10.1186/1472-6882-14-280) contains supplementary material, which is available to authorized users.

It has been shown that elevation of plasma methionine (Met) and its metabolites may occur in several genetic abnormalities. In this study we investigated the in vitro and in vivo effects of the Met and methionine sulfoxide (MetO) on oxidative stress parameters in the liver of rats. For in vitro studies, liver homogenates were incubated with Met, MetO, and Mix (Met + MetO). For in vivo studies, the animals were divided into groups: saline, Met 0.4 g/kg, MetO 0.1 g/kg, and Met 0.4 g/kg + MetO 0.1 g/kg. The animals were euthanized 1 and 3 h after injection. In vitro results showed that Met 1 and 2 mM and Mix increased catalase (CAT) activity. Superoxide dismutase (SOD) was enhanced by Met 1 and 2 mM, MetO 0.5 mM, and Mix. Dichlorofluorescein oxidation was increased by Met 1 mM and Mix. In vivo results showed that Met, MetO, and Mix decreased TBARS levels at 1 h. Total thiol content decreased 1 h after and increased 3 h after MetO and Met plus MetO administrations. Carbonyl content was enhanced by Met and was reduced by MetO 1 h after administration. Met, MetO and Met plus MetO decreased CAT activity 1 and 3 h after administration. Furthermore, only MetO increased SOD activity. In addition, Met, MetO, and Mix decreased dichlorofluorescein oxidation at 1 and 3 h. Our data indicate that Met/MetO in vivo and in vitro modify liver homeostasis by altering the redox cellular state. However, the hepatic changes caused by these compounds suggest a short-time adaptation of this tissue.

High plasma levels of methionine (Met) and its metabolites such as methionine sulfoxide (MetO) may occur in several genetic abnormalities. Patients with hypermethioninemia can present neurological dysfunction; however, the neurotoxicity mechanisms induced by these amino acids remain unknown. The aim of the present work was to study the effects of Met and/or MetO on oxidative stress, genotoxicity, cytotoxicity and to evaluate whether the cell death mechanism is mediated by apoptosis in the cerebral cortex of young rats. Forty-eight Wistar rats were divided into groups: saline, Met 0.4 g/Kg, MetO 0.1 g/Kg and Met 0.4 g/Kg + MetO 0.1 g/Kg, and were euthanized 1 and 3 h after subcutaneous injection. Results showed that TBARS levels were enhanced by MetO and Met+MetO 1 h and 3 h after treatment. ROS was increased at 3 h by Met, MetO and Met+MetO. SOD activity was increased in the Met group, while CAT was reduced in all experimental groups 1 h and 3 h after treatment. GPx activity was enhanced 1 h after treatment by Met, MetO and Met+MetO, however it was reduced in the same experimental groups 3 h after administration of amino acids. Caspase-3, caspase-9 and DNA damage was increased and cell viability was reduced by Met, MetO and Met+MetO at 3 h. Also, Met, MetO and Met+MetO, after 3 h, enhanced early and late apoptosis cells. Mitochondrial electrochemical potential was decreased by MetO and Met+MetO 1 h and 3 h after treatment. These findings help understand the mechanisms involved in neurotoxicity induced by hypermethioninemia.

In order to clarify the molecular mechanisms of Sn(2+) genotoxicity, we evaluated the induction of strand breaks, formamidopyrimidine DNA glycosylase (Fpg) and endonuclease III (Endo III) sensitive sites, and the interference with the repair of methyl methane sulfonate (MMS)-caused DNA damage in V79 Chinese hamster lung fibroblasts exposed to stannous chloride by comet assay. A concentration-related increase in the DNA damage induced by 2 h SnCl(2) treatment at a concentration range of 50-1,000 microM was observed (r = 0.993; P < 0.01). Significantly elevated DNA migration in relation to the control level was detected at doses 100, 500 and 1,000 microM in normal alkaline and at doses 500 and 1,000 microM in modified (with Fpg and Endo III) comet assay. Although 50 microM SnCl(2) concentration did not increase significantly the DNA migration by itself in comet assay, it was capable to inhibit the repair of MMS-induced DNA damage during the post-treatment period of 24 h. Our results demonstrate the genotoxic and comutagenic effects of stannous chloride in V79 cells. The inhibitory effect of Sn(2+) on repair of MMS-induced DNA damage suggests that this metal can also interfere in DNA repair systems thus contributing to increased mutation by shifting the balance from error-free to error-prone repair processes.

The diphenyl ditelluride (DPDT) is a prototype for the development of new biologically active molecules. In previous studies, DPDT showed an elevated cytotoxicity in Chinese hamster fibroblast (V79) cells but the mechanisms for reduction of cell viability still remain unknown. DPDT showed mutagenic properties by induction of frameshift mutations in bacterium Salmonella typhimurium and yeast Saccharomyces cerevisiae. This organotelluride also induced DNA strand breaks in V79 cells. In this work, we investigated the mechanism of DPDT cytotoxicity by evaluating the effects of this compound on cell cycle progression, apoptosis induction and topoisomerase I inhibition. Significant decrease of V79 cell viability after DPDT treatment was revealed by MTT assay. Morphological analysis showed induction of apoptosis and necrosis by DPDT in V79 cells. An increase of caspase 3/7 activity confirmed apoptosis induction. The cell cycle analysis showed an increase in the percentage of V79 cells in S phase and sub-G1 phase. The yeast strain deficient in topoisomerase I (Topo I) showed higher tolerance to DPDT compared with the isogenic wild-type strain, suggesting that the interaction with this enzyme could be involved in DPDT toxicity. The sensitivity to DPDT found in top3Δ strain indicates that yeast topoisomerase 3 (Top3p) could participate in the repair of DNA lesions induced by the DPDT. We also demonstrated that DPDT inhibits human DNA topoisomerase I (Topo I) activity by DNA relaxation assay. Therefore, our results suggest that the DPDT-induced cell cycle arrest and reduction in cell viability could be attributed to interaction with topoisomerase I enzyme.

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