Tri-chalcone suppressed breast cancer cell proliferation and induced apoptosis through intrinsic and extrinsic pathways.

Breast cancer development depends critically on antiproliferative and apoptotic mechanisms. However, the mechanisms underlying the antiproliferative and apoptosis effects of breast cancer treated with tri-chalcone remain unclear. Tri-chalcones have been demonstrated in prior studies to inhibit the proliferation of breast cancer cells (MCF-7). Following the discovery, this study seeks to investigate the effect of tri-chalcone compounds on targets involved in antiproliferative and apoptosis mechanisms. In this study, we employed bioinformatics analysis along with in vitro evaluation using tri-chalcone-treated MCF-7 cells to determine the responses of antiproliferative and apoptosis mechanisms. The analysis revealed that the compounds interact with six apoptosis target receptors: TNFα, Bak, Bcl-2, caspase-9, and caspase-8. Tri-chalcone S1-2 exhibited the strongest binding affinities for TNFα (-7.39 kcal/mol), caspase-8 (-8.43 kcal/mol), caspase-9 (-8.53 kcal/mol), Bcl-2 (-8.51 kcal/mol), and Bak (-7.15 kcal/mol). The tri-chalcone S1-2 paired with the corresponding proteins showed minor flexibility and extremely small changes of less than 0.25 nm during the MD simulation. Additionally, tri-chalcone S1-2 had a significant inhibitory effect on the proliferation of MCF-7 cells (5.31 ± 0.26 µg/mL) compared to other compounds. S1-2 also induced apoptosis, affecting nearly half (43.80%) of the total early and late apoptosis in MCF-7 cells. S1-2-treated MCF-7 cells also demonstrated upregulations of genes TNFα (1.50), Bak (1.42), caspase-8 (1.24), and caspase-9 (1.61), accompanied by a downregulation of gene Bcl-2 (0.71). The discovery gives us a better understanding of how tri-chalcone S1-2 suppressed MCF-7 cell proliferation and induced apoptosis through intrinsic and extrinsic pathways.

Investigating the potential of mono-chalcone compounds in targeting breast cancer receptors through network pharmacology, molecular docking, molecular dynamics simulation, antiproliferative effects, and gene expressions.

The study aims to investigate various aspects of synthesized mono-chalcone compounds 5 and 8 concerning breast cancer, including network pharmacology, molecular docking, molecular dynamics (MD) simulations, antiproliferative effects, and gene expressions. Initially, the compounds underwent a network pharmacology analysis targeting breast cancer-related targets, with MalaCards, SwissTargetPrediction, and PharmMapper identifying 70 breast cancer target receptors. Subsequently, protein-protein interaction (PPI) network analysis revealed two distinct target gene clusters. Survival analysis identified seven significant target genes following Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and Gene Ontology (GO) evaluation. Molecular docking and MD simulations were conducted on these seven target genes (AKT2, BRAF, ESR1, FGFR1, IGF1, IGF1R, and KIT), revealing that compound 8 exhibited the highest binding affinities, as well as better stability and compactness when interacting with the targeted proteins. Next, the compounds underwent cell viability assay and gene expression analysis to validate the in silico findings. Both compounds demonstrated the ability to suppress breast cancer proliferation, with compound 8 showing increased selectivity in targeting breast cancer cells while causing minimal harm to normal breast cells. The suppression of breast cancer cell proliferation was attributed to decreased expression levels of AKT2, BRAF, FGFR1, IGF1, IGF1R, KIT, and ESR1. Hence, the results provide insights into the molecular interaction responsible for the anti-breast cancer capabilities of mono-chalcone compounds. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03991-y.

Network pharmacology, molecular docking and molecular dynamics simulation of chalcone scaffold-based compounds targeting breast cancer receptors.

Compounds with a chalcone scaffold-based structure have demonstrated promising anticancer biological activity. However, the molecular interactions between chalcone scaffold-based compounds and breast cancer-associated proteins remain unclear. Through network pharmacology, molecular docking, and molecular dynamics (MD) simulation analyses, compounds with a chalcone scaffold-based structure were evaluated for their interaction with potential breast cancer targets. The compounds were retrieved from the ASINEX database, resulting in 575,302 compounds. A total of 342 compounds with chalcone scaffold-based structures were discovered. From the 342 compounds that was analysed, ten were chosen due to their adherence to Lipinski's rule, having an appropriate range of lipophilicity (LOGP), and topological polar surface area (TPSA), and absence of any toxicity. Based on target intersection, 50 target genes were found and subjected to protein-protein interaction (PPI), gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Four target genes were found to be involved in the breast cancer pathway. Consequently, molecular docking was utilised to analyse the molecular interactions between the compounds and four target protein receptors. Compound 211 exhibited the highest binding affinities for the epidermal growth factor receptor (EGFR), fibroblast growth factor receptor 1 (FGFR1), oestrogen receptor (ESR1), and cyclin dependent kinase 6 (CDK6) with values of -8.95 kcal/mol, -8.60 kcal/mol, -10.33 kcal/mol, and -9.90 kcal/mol, respectively. During MD simulation, compound 211 and its respective proteins were stable, compact, and had minimal flexibility. The findings provide foundations for future studies into the interaction underlying the anti-breast cancer potential of compounds with chalcone-based scaffold structures.Communicated by Ramaswamy H. Sarma.

Low cytotoxicity, and antiproliferative activity on cancer cells, of the plant Senna alata (Fabaceae) / Baja citotoxicidad, y actividad antiproliferativa sobre las células cancerosas, de la planta Senna alata (Fabaceae)

Introduction: The leaves of Senna alata from the Fabaceae family have been used in folk medicine for the cure of skin disease. In this study, we tested the extract and fractions on brine shrimp lethality test and antiproliferative activity on cancer and normal cell lines. Objective: In this study, we assessed the cytotoxicity of S. alata using brine shrimp test and two cell lines. Methods: The 80 % ethanolic leaf extract and its fractions were examined for possible cytotoxic effect using sulforhodamine B (SRB) cytotoxicity assay towards breast cancer (MCF-7), normal (MCF10A) cell lines, and brine shrimp lethality test (BSLT). Results: The brine shrimp lethality bioassay exhibits no cytotoxicity even at high concentration (5 000 µg/mL). The LC50 for dichloromethane, chloroform, butanol, and aqueous were > 1 000 µg/mL (non-toxic). The IC50 for in vitro SRB cytotoxicity against MCF-7 for n-hexane was 0.013 µg/mL, which was considered highly toxic, while dichloromethane and chloroform recorded at 47.11 and 57.61 µg/mL, respectively after 72 hours exposure time although there was no cytotoxicity found on the normal cell line. Conclusion: This study shows that S. alata crude ethanolic leaf extract and its fractions potentially contain significant bioactive compounds that are safe from adverse effects, which proves the therapeutic application of S. alata in traditional remedy.

Introducción: Las hojas de Senna alata de la familia Fabaceae se han utilizado en la medicina popular para la cura de enfermedades de la piel. En este estudio, probamos el extracto de la planta en líneas celulares normales y cancerosas. Objetivo: Evaluamos la citotoxicidad de S. alata usando una prueba del camarón Artemia y la actividad antiproliferativa. Métodos: El extracto de hoja etanólico al 80 % y sus fracciones se examinaron en busca de un posible efecto citotóxico utilizando un ensayo de citotoxicidad de sulforrodamina B (SRB) frente a líneas celulares de cáncer de mama (MCF-7), normales (MCF10A) y prueba de letalidad del camarón Artemia (BSLT). Resultados: El bioensayo de letalidad del camarón Artemia no presenta citotoxicidad incluso en alta concentración (5 000 µg/mL). La CL50 para diclorometano, cloroformo, butanol y acuoso fue > 1000 µg/mL (no tóxico). La CI50 para la citotoxicidad in vitro de SRB contra MCF-7 para n-hexano fue de 0.013 µg/mL, que se consideró altamente tóxica, mientras que el diclorometano y el cloroformo registraron 47.11 y 57.61 µg/mL, respectivamente, después de 72 horas de tiempo de exposición, aunque no hubo citotoxicidad encontrada en la línea celular normal. Conclusión: Este estudio muestra que el extracto de hoja etanólico crudo de S. alata y sus fracciones contienen potencialmente compuestos bioactivos significativos que están a salvo de efectos adversos, lo que demuestra la aplicación terapéutica de S. alata como remedio tradicional.