RESUMO
Cell division cycle 20 (CDC20), a critical partner of anaphase promoting complex (APC/C), is indispensably required for metaphase-to-anaphase transition. CDC20 overexpression in TNBC breast cancer patients has been found to be correlated with poor prognosis, hence, we aimed to target CDC20 for TNBC therapeutics. In silico molecular docking of large-scale chemical libraries (phytochemicals/synthetic drugs) against CDC20 protein structure identified five synthetic drugs and four phytochemicals as potential hits interacting with CDC20 active site. The molecular selection was done based on docking scores, binding interactions, binding energies and MM/GBSA scores. Further, we analysed ADME profiles for all the hits and identified lidocaine, an aminoamide anaesthetic group of synthetic drug, with high drug-likeness properties. We explored the anti-tumorigenic effects of lidocaine on MDA-MB-231 TNBC breast cancer cells, which resulted in increased growth inhibition in dose-dependent manner. The molecular mechanism behind the cell viability defect mediated by lidocaine was found to be induction of G2/M cell cycle arrest and cellular apoptosis. Notably, lidocaine treatment of TNBC cells also resulted in downregulation of CDC20 gene expression. Thus, this study identifies lidocaine as a potential anti-neoplastic agent for TNBC cells emphasizing CDC20 as a suitable therapeutic target for breast cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03554-7.
RESUMO
New targeted therapy for triple negative breast cancer (TNBC) is an urgent need, as advanced disease responds poorly to conventional chemotherapy. Genomic and proteomic studies are currently investigating new genes and proteins as promising therapeutic targets. One of such therapeutic targets is a cell cycle regulatory kinase; Maternal Embryonic Leucine Zipper Kinase (MELK), overexpressed in TNBC and correlated with cancer development. We performed molecular docking for virtual screening of chemical libraries (phytochemicals/synthetic drugs) against MELK protein structure and identified 8 phytoconstituents (isoxanthorin, emodin, gamma-coniceine, quercetin, tenuazonic acid, isoliquiritigenin, kaempferol, and Nobiletin) and 8 synthetic drugs (tetrahydrofolic acid, alfuzosin, lansoprazole, ketorolac, ketoprofen, variolin B, orantinib, and firestein) as potential hits interacting with the active site residues of MELK based on bound poses, hydrogen bond, hydrophobic interactions and MM/GBSA binding free energies. ADME and drug-likeness prediction further identified few hits with high drug-likeness properties and were further tested for anti-tumorigenic potential. Two phytochemicals isoliquiritigenin and emodin demonstrated growth inhibitory effects on TNBC MDA-MB-231 cells while much lower effect was observed on non-tumorigenic MCF-10A mammary epithelial cells. Treatment with both molecules downregulated MELK expression, induced cell cycle arrest, accumulated DNA damage and enhanced apoptosis. The study identified isoliquiritigenin and emodin as potential MELK inhibitors and provides a basis for subsequent experimental validation and drug development against cancer.
Assuntos
Emodina , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteínas Serina-Treonina Quinases/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Simulação de Acoplamento Molecular , Emodina/farmacologia , Proteômica , Proliferação de Células , Detecção Precoce de Câncer , Linhagem Celular TumoralRESUMO
Herein, we introduce an eco-friendly electrochemical sensor based on melamine-enriched nitrogen-doped carbon nanosheets decorated with gold nanoparticles (Au-CNSm) for arsenic sensing. An extremely facile, low-toxicity, biocompatible, and affordable hydrothermal technique was adopted for the synthesis of the Au-CNSm nanocomposite. The Au-CNSm-integrated sensing platform was optimized for electrode composition by cyclic voltammetry (CV). Owing to the synergistic effects of melamine-enriched carbon nanosheets (CNSm) and gold nanoparticles (AuNPs), the anodic peak current increased in the Au-CNSm-modified sensing electrode as compared to the CNSm-decorated platform. A wide linear range of 0.0001-100 µM and a low detection limit of 0.0001 µM were obtained. The visual signals can be measured at a very minute concentration of 0.0001 µM (0.1 ppb) on a screen-printed carbon electrode (SPCE) modified with Au-CNSm. Hence, this electrode system clearly outperformed the previously reported studies in terms of linear range, limit of detection (LOD), and electrocatalytic activity for arsenic sensing. Interestingly, the fabricated biosensor can be developed as a point-of-care device for real-time environmental monitoring for public safety. Henceforth, owing to exceptional attributes such as portability, selectivity, and sensitivity, this device offers great promise in modeling a revolutionary new class of electrochemical sensing platforms for an ultrasensitive and reliable detection strategy for arsenite (As(III)).