Mechanistic insights into deoxynivalenol-induced cytotoxicity in an SH-SY5Y 3D spheroid model.

Hallachrome, a marine anthraquinone, impairs cell proliferation by acting as a functional mitochondrial uncoupler in A375 melanoma cells

Background Melanoma remains one of the most lethal cancers due to its high metastatic capacity and resistance to current therapies, emphasizing the need for novel antineoplastic agents, including bioactive molecules from marine organisms, as potential sources of anticancer compound. Aims This study aimed to investigate, for the first time, the anticancer potential of Hallachrome (HC), an anthraquinone derived from the marine polychaete Halla parthenopeia, in A375 melanoma cells. Methods A375 melanoma cells were treated with HC in vitro to evaluate its impact on cell proliferation, migration, and morphology. Proteomic analysis was carried out to identify differentially expressed proteins in order to elucidate the biological processes modulated by the treatment. Mitochondrial morphology and function were analyzed by confocal microscopy and oxygen consumption rate, respectively, while mitochondrial membrane potential, intracellular reactive oxygen species (ROS) levels and GSH/GSSG ratio were evaluated by fluorescence-based assays. Results HC treatment significantly reduced melanoma cell proliferation and migration in vitro, accompanied by morphological alteration and apoptosis death. Proteomic profiling revealed differential expression of several proteins involved, for example, in membrane and mitochondria organization. Moreover, HC treatment induced severe mitochondrial dysfunction, characterized by ATP depletion, mitochondrial membrane depolarization, fragmentation of the mitochondrial network, altered intracellular ROS level and GSH/GSSG ratio. Discussion These findings suggest that HC inhibits melanoma cell survival by disrupting mitochondrial homeostasis and inducing energetic stress. Given the pivotal role of mitochondria in cancer progression, the ability of HC to interfere with mitochondrial functions supports its potential as a promising anticancer agent.

A mechanistic approach about oxidative, mutagenic, and cytotoxic effects of an organotellurane.

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 IC50 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 (LC50 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.

against rotenone-induced cytotoxicity protects human dopaminergic neuroblastoma SH-SY5Y cell line

Amphiphilic Semisynthetic Triterpenoids Impair Survival Pathways and Suppress Clonogenic Growth in Multidrug-Resistant High-Risk Neuroblastoma

High-risk neuroblastoma (HR-NB) remains a major clinical challenge due to the emergence of therapy resistance. In this study, the anticancer effects of seven previously synthesized betulin (BET), betulinic acid (BA) and ursolic acid (UA) derivatives (1–7) and of their natural precursors BET, BA and UA (8–10) were investigated in HTLA NB cells, selected as the experimental model by MTT assay, to find a possible solution to drugs that have lost their effect. Dynamic light scattering (DLS) analysis showed that amphiphilic compounds 1 and 4–7 form nanovesicles (240–448 nm) in water, while all compounds have high positive ζ-potential (ζ-p, +28.5–+83.1 mV), supporting favourable membrane interaction and cellular uptake. Cytotoxic experiment results and related IC50 values were expressed as the mean ± SD of four independent experiments run in triplicate. Most derivatives exhibited a cytotoxic activity higher than that of their natural precursors and outperformed etoposide; they were particularly effective against the multidrug resistant (MDR) HTLA ER cells. Among them, the ursolic acid (UA) derivative 7 emerged as the most active compound, displaying sub-micromolar to low micromolar IC50 values and markedly improving the activity of native UA. Functional studies revealed that it induces complete suppression of clonogenic growth at low micromolar concentrations in both HTLA ER and parental HTLA 230 NB cells. In addition, a concentration-dependent downregulation of Akt, p-Akt, BMI1 and PARP, was observed consistently with a marked suppression of survival pathways and loss of cellular homeostasis. Collectively, our experiments, which need further direct investigation to confirm subsequent assumption, could suggest that compound 7 could kill cancer cells via a non-apoptotic, bioenergetic collapse mechanism. All of these findings suggest compound 7 as a promising mitochondria-targeted lead candidate and support amphiphilic triterpenoid derivatives as attractive platforms for overcoming multidrug resistance in high-risk NB.

Structure-Dependent Cytotoxic and Cytoprotective Effects of Molybdenum(VI) Schiff Base Complexes in the Neuronal Cells In Vitro

Coordination compounds with transition metals, especially of molybdenum, are promising cytoprotective agents. In this work, we analyzed the changes in HT-22 cell viability under the influence of molybdenum(VI) Schiff base complexes per se or in cellular injury induced by hydrogen peroxide (annexin V and propidium iodine staining assay). The results allowed to identify the most active compound with dioxidomolybdenum(VI) ion coordinated to Schiff base derived from 1S,2S-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol and 5-methoxysalicylaldehyde, protecting the cells and possessing low cytotoxicity. We addressed a range of active concentrations (statistically significant effect from 5 µM to 50 µM) and the temporal characteristics of the effect (which is evident in 1-h preincubation regimen or adding the compound 1 h after hydrogen peroxide). Importantly, the effect was present at different levels of glucose in the medium and in cellular injury induced by glutamate. Less pronounced protective effect was seen in SH-SY5Y cells on the model of hydrogen peroxide-induced (but not in glutamate-induced) cytotoxicity. Among the possible mechanisms of cytoprotective activity, there is a direct interaction with hydrogen peroxide (measured by cyclic voltammetry), decrease in reactive oxygen species generation (DCFH-DA assay in HT-22 cells) and maintenance of catalase activity (assessed in lysates of HT-22 cells on the model of hydrogen peroxide-induced injury).

In vitro toxicity of piperazine derivatives involves mitochondrial dysfunction and microtubule-related changes in neuronal cell models

Piperazine derivatives such as BZP and TFMPP have been used as “party pill” substitutes for MDMA and are associated with neurological and cardiovascular toxicity. While their psychoactive effects are largely attributed to monoaminergic mechanisms, the cellular pathways underlying their toxicity are less well defined. Previous in vitro studies indicate mitochondrial dysfunction and oxidative stress, but potential effects on the neuronal cytoskeleton, specifically microtubules, have not been systematically investigated. The effects of MeOPP, BZP, pFPP and TFMPP were evaluated in retinoic acid–differentiated P19 mouse embryonal carcinoma–derived neurons using complementary assays of cell viability (calcein-AM), metabolic activity (MTT), membrane integrity (LDH), mitochondrial membrane potential (TMRE) and βIII-tubulin immunofluorescence. Key findings were evaluated in differentiated human SH-SY5Y neuroblastoma cells and in Caco-2 human colorectal adenocarcinoma cells. Tubulin polymerization was assessed in a complementary cell-free assay. All compounds induced concentration-dependent toxicity, with marked differences in potency and efficacy. TFMPP was the most active compound across endpoints, producing early and sustained loss of mitochondrial membrane potential followed by reduced viability, cytoskeletal changes and increased membrane damage. BZP and pFPP showed moderate toxicity at higher concentrations, whereas MeOPP had limited effects. Time-course analysis demonstrated that mitochondrial depolarization preceded membrane damage. Reduced βIII-tubulin immunofluorescence in neuronal cells, together with inhibition of tubulin polymerization in a cell-free system, is consistent with effects on microtubule-related processes. Similar toxicity patterns were observed in SH-SY5Y cells, and cytotoxic effects of BZP and TFMPP were also detected in Caco-2 cells. Piperazine derivatives are associated with cellular toxicity characterized by early mitochondrial dysfunction and subsequent effects on the neuronal cytoskeleton. TFMPP showed the most consistent activity across models. The findings indicate that microtubule-related processes may contribute to toxicity and support further mechanistic studies beyond monoaminergic pathways.