Antonielly Campinho dos Reis

Organotellurium (OTe) compounds have pharmacological properties, including leishmanicidal, antimalarial, and antifungal activities. Herein, we assessed cytotoxicity effects of OTe RF07 in a panel of tumor cell lines, as well as its oxidative, toxicity, and hemolytic actions. The toxicity was evaluated on Allium cepa and Artemia salina larvae. Cell viability was also assessed by resazurin in murine cells (Sarcoma 180), human cells (HL-60, leukemia; AGP01, gastric adenocarcinoma; SKMEL-28, human melanoma; MRC-5, normal fibroblasts), and dog erythrocytes. The oxidative capacity of RF07 was evaluated by wild-type and antioxidant-mutated enzyme strains of Saccharomyces cerevisiae . RF07 presented cytotoxic action on all normal and tumor cells, whose IC ₅₀ ranged from 0.07 μg/mL (HL-60) to 73.45 μg/mL (Sarcoma 180) and toxicological activity on A. salina nauplii in a concentration-dependent manner after exposure for 24 h and 48 h (LC ₅₀ values of 15.02 and 5.43 μg/mL for 24 h and 48 h, respectively). Moreover, RF07 reduced mitotic index of meristematic A. cepa cells at 5, 10 and 20 μg/mL, caused arrest in interphase, and increased chromosomal changes, including micronucleus, c -metaphases, and chromosomal bridges, loss, and delays. In summary, RF07 exhibits antiproliferative action on animal cells, high toxicity on Artemia salina nauplii, as well as clastogenic effects on growing roots. This antimitotic action is not related to direct membrane damage, although it relies on chromosomal injuries and may be related to the induction of oxidative stress as observed in yeast cells.

This study aimed to synthesize a liposomal nanoformulation containing citrinin (LP-CIT) to improve its availability and to evaluate its toxicogenomic profile, focusing on cytotoxic and genotoxic effects in breast cancer (MDA-MB-231) and non-tumorigenic mammary epithelial (MCF-10A) cell lines. The formulation was characterized by macroscopic appearance, pH, particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency, and estability of nanoparticles. Citrinin content, encapsulation efficiency, and liposome stability were evaluated. Cytotoxicity was assessed using MTT, trypan blue exclusion, and flow cytometry. Cell death mechanisms were investigated by mitochondrial membrane potential analysis and expression of apoptotic markers (caspase-9 and BAX). Genotoxicity was evaluated using the comet assay. The liposomal nanosystem consisted of small unilamellar vesicles with a mean diameter of 143.3 nm, a PDI of 0.3, and a positive surface charge (+ 28.5 mV). The average was 63.69 ± 0.18% of citrinin encapsulated in liposomes with stability more than 21 days. Both free citrinin (CIT) and LP-CIT showed cytotoxic effects in MDA-MB-231 and MCF-10A cells, with lower LC₅₀ values observed for LP-CIT. Although LP-CIT induced more pronounced cytotoxic and genotoxic effects in the cancer cell line, toxic effects were also observed in non-tumorigenic cells, indicating limited selectivity. Cell death was associated with mitochondrial membrane depolarization and increased caspase-9 and BAX expression. Both formulations induced DNA damage as detected by the comet assay. Liposomal encapsulation enhanced citrinin biological activity but did not indicate tumor selectivity. Thus, this study represents a toxicogenomic assessment of citrinin and its liposomal formulation for potential therapeutic applicability.

Stevia urticifolia Thunb. is an underexploited herb possessing bioactive flavonoids, saponins, and terpenoids. The aim of this study was to examine the antiproliferative and toxicogenetic properties of the ethyl acetate extract from Stevia urticifolia aerial parts (EtAcSur) upon Artemia salina, erythrocytes, Allium cepa and sarcoma 180 cells and fibroblasts, as well as in vivo studies on mice to determine systemic, macroscopic, and behavioral alterations and bone marrow chromosomal damage. The assessment using A. salina larvae and mouse blood cells revealed LC₅₀ and EC₅₀ values of 68.9 and 113.6 µg/ml, respectively. Root growth and mitosis were inhibited by EtAcSur, and chromosomal aberrations were detected only at 100 μg/ml. EtAcSur exhibited potent concentration-dependent viability reduction of S180 and L-929 cells and antioxidant capacity employing ABTS^• and DPPH^•. No previous in vivo studies were performed before with the EtAcSur. Signals of acute toxicity were not observed at 300 mg/kg. Physiological and toxicological investigations at 25 and 50 mg/mg/day i.p. for 8 days did not markedly change body or organ relative weights, nor patterns of spontaneous locomotor and exploratory activities. In contrast, clastogenic effects on bone marrow were found at 50 mg/mg/day. EtAcSur was found to (1) produce toxicity in microcrustaceans, (2) capacity as free radical scavenger, (3) antimitotic, cytotoxic and clastogenic activties upon vegetal and mammalian cells, and (4) lethality on both tumor and normal murine cells indistinctly. In vivo damage systemic effects were not remarkable and clinical signals of toxicity were not observed, suggesting the significant pharmacological potential of S. urticifolia for the development of antineoplastic agents. Abbreviations: ABTS: 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid); DMSO: dimethylsulfoxide; DPPH: 1,1-diphenyl-2-picrylhydrazyl; EC₅₀: effective concentration 50%; EtAcSur: ethyl acetate extract from Stevia urticifolia aerial parts; Hb, hemoglobin; IC₅₀: inhibitory concentration 50%; LC₅₀,: lethal concentration 50%; MI: mitotic index; RBC, red blood cells; Trolox: 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid.

Background: The search for novel metallic chemical compounds with toxicogenic effects has been of great importance for more efficient cancer treatment. Objective: The study evaluated the cytotoxic, genotoxic and mutagenic activity of organoteluran RF07 in the S-180 cell line. Methods: The bioassays used were cell viability with 3-(4,5-dimethyl-2-thiazole)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) test, evaluation of apoptosis and necrosis using fluorescence and flow cytometry, cytokinesisblock micronucleus test and comet assay. The compound was tested at 1; 2.5 and 5μM. Results: The results showed the cytotoxicity of RF07 at concentrations of 2.5, 5, 10 and 20μM when compared to the negative control. For genotoxicity tests, RF07 showed effects in all concentrations assessed by increased index and frequencies of damage and mutagenic alterations. The compound was also cytotoxic due to the significant decrease in the nuclear division index, with significant values of apoptosis and necrosis. The results of fluorescence and flow cytometry showed apoptosis as the main type of cell death caused by RF07 at 5μM, which is thought to avoid an aggressive immune response of the organism. Conclusion: In addition to cytotoxic and genotoxic effects, RF07 creates good perspectives for future antitumor formulations.