Flavone cirsimarin impairs cell proliferation, migration, and invasion in MCF-7 cells grown in 2D and 3D models. (September 2022)

• Record Type: Journal Article
• Authors: Serpeloni, Juliana Mara; Oliveira, Larissa Cristina Bastos de; Fujiike, Andressa; Tuttis, Katiuska; Ribeiro, Diego Luis; Camara, Marcos Bispo Pinheiro; Rocha, Claudia Quintino da; Cólus, Ilce Mara de Syllos
• Is Part Of: Toxicology in vitro. Volume 83(2022)
• Publication Date: 2022-09
• Subjects: Anti-metastatic -- Cytotoxicity -- Cirsitakaoside -- Genotoxic -- Phytotherapy -- Scoparia dulcis L; AKT AKT serine/threonine kinase -- BAX BCL2 associated x, apoptosis regulator -- BCL2L1 BCL2 like 1 -- BIRC5 baculoviral inhibitor of apoptosis repeat-containing 5 -- BSA bovine serum albumin -- CASP9 caspase 9 -- CBioPortal cBioPortal for cancer genomics -- CCNA2 cyclin A2 -- CCND1 cyclin D1 -- CCR5 C-C motif chemokine receptor 5 -- CDH1 cadherin 1 -- CDK2 cyclin-dependent kinase 2 -- CDK4 cyclin-dependent kinase 4 -- CIR cirsimarin -- CM-H2DCFDA 5- (and-6) -chloromethyl-2′, 7′-dichlorodihydrofluorescein diacetate, acetyl ester -- DMEM Dulbecco's Modified Eagle's Medium -- DMSO dimethyl sulfoxide -- DT docetaxel -- DXR doxorubicin -- EMT epithelial–mesenchymal transition -- FBS fetal bovine serum -- FC fold change -- GAPDH glyceraldehyde-3-phosphate dehydrogenase -- GPX1 glutathione peroxidase 1 -- HPLC-PDA quantitative high-performance liquid chromatography photo-diode array -- HPRT1 hypoxanthine guanine phosphoribosyl transferase 1 -- IC50 half-maximal inhibitory concentration -- LMP low melting point agarose -- MCTSs three-dimensional multicellular tumor spheroids -- MMP11 matrix metallopeptidase 11 -- MMP9 matrix metallopeptidase 9 -- MUC1 Mucin 1, cell surface associated -- PBS phosphate buffered saline -- PI3K phosphatidylinositol-4, 5-bisphosphate 3-kinase -- ROS reactive oxygen species -- RPS18 ribosomal Protein S18 -- RT-qPCR real-time quantitative polymerase chain reaction -- TNF tumor necrosis factor-α -- TP53 tumor protein P53; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2022.105416
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: The present study investigates the mechanisms underlying the in vitro antitumoral activity of cirsimarin (CIR 10 to 320 μM), a flavone extracted from the aerial parts of Scoparia dulcis L., on MCF-7 cells cultured in 2D and multicellular tumor spheroids (3D). CIR (from 40 μM) decreased cell viability in the resazurin assay and colony formation in the 2D model. In the same way, in the 3D model, CIR (from 40 μM) induced cell death (triple staining assay) and decreased spheroid integrity after 16 days with no induction of intracellular reactive species (CM-H2 DCFDA). In 2D, CIR decreased the invasion (transwell) and horizontal migration (wound healing), while in 3D, CIR diminished cell migration (ECM® gel) and induced DNA damage (comet assay) possibly related to cell death. CIR mediated antitumoral effects in 3D spheroids by negative modulation of genes associated with cell proliferation ( CCND1, CCNA2, CDK2, CDK4, and TNF ) and death ( BCL-XL, BAX, CASP9, and BIRC5). BIRC5 and CDK s inhibitors have been proposed as versatile anticancer drugs, which makes our results quite interesting. TNF negative modulation may also be related to the downregulation of MMP9 and MMP11 and anti-migration/invasion of MCF-7 cells cultured in 2D and 3D models. These are relevant properties for long-term strategies to avoid metastasis and improve the prognosis of breast cancer. Graphical abstract: Unlabelled Image Highlights: Cirsimarin has low cytotoxicity, antiproliferative, and anti-migratory effects in vitro. MCF-7 cells grown in a 3D model show greater resistance to cirsimarin-cytotoxicity. Antiproliferative effects are related to the modulation of cell cycle genes. Downregulation of TNF-α and metalloproteinases are related to anti-migratory effects. Cirsimarin may improve the prognostic states in breast cancer.