Assessment of abiraterone (ABI) tumor cell activity via in vitro models of androgen (A)-responsive prostate cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15166-e15166
Author(s):  
Ian Hickson ◽  
Ann Marien ◽  
Maarten Derks ◽  
Marc Janssen
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Tumor Cells ◽  
In Vitro Models ◽  
Reporter Assay ◽  
Lncap Cells ◽  
Affymetrix Microarray ◽  
3D Cultures ◽  
2D And 3D

e15166 Background: Inhibition of CYP17 by abiraterone acetate (AA) blocks A biosynthesis, reduces A levels and results in inhibition of A-dependent tumor growth. AA has been shown to improve survival in patients with metastatic castrate-resistant prostate cancer (HR = 0.74) (Scher, ASCO 2011). AA is converted to ABI in vivo. This study investigates whether direct effects of ABI on tumor cells (ie, blockade of intratumoral A synthesis) may contribute to the clinical efficacy of AA using in vitro models. Methods: LNCaP cells (human prostate cancer cell line [HPCCL]) were grown in 2D and 3D cultures, and ABI activity was assessed by reduction of androgen receptor (AR) output in gene expression profiling (Affymetrix microarray), reporter assay, and by immunoblot for A-responsive signals. Using ABI-sensitive LNCaP cells, responses were further characterized in the presence or absence of ligand (dihydrotestosterone [DHT]) and with A-targeting agents TOK-001 and MDV3100. Results: ABI exposure resulted in dose-dependent modulation of A-dependent gene expression in Affymetrix microarray analysis of 2D and 3D cultures. Similar results were seen in an analysis of AR-dependent protein and in an AR-driven reporter assay in 2D LNCaP or VCaP (another HPCCL) cell culture. In LNCaP, AR output was inhibited by low concentrations of ABI (IC50 100-300 nM), comparable to TOK-001 (IC50 30-100 nM) and less potent than MDV3100 (IC50 10-30 nM). Growth inhibition (MTT assay) occurred at concentrations 10-fold higher for all compounds. For ABI and TOK-001, inhibition of AR output was reduced by DHT (30- to 100-fold increase in IC50); with MDV3100, the shift in IC50 was less (10-fold) with agonism of AR output at low nM concentrations. Conclusions: ABI has an inhibitory effect on AR output in LNCaP cells. Partially overcoming this inhibition through addition of DHT implies that CYP17 inhibition and the subsequent A reduction play a role in the intratumoral activity of AA. However, persistent inhibition of AR output in the presence of DHT implies additional anti-A effects of AA in prostate tumor cells. This model may provide a useful tool for the study of AR-targeted therapies, combinations of agents, and resistance to agents targeting A.

scholarly journals 3D Bone Morphology Alters Gene Expression, Motility, and Drug Responses in Bone Metastatic Tumor Cells

2020 ◽  
Vol 21 (18) ◽  
pp. 6913
Author(s):  
Ushashi C. Dadwal ◽  
Alyssa R. Merkel ◽  
Jonathan M. Page ◽  
Kristin A. Kwakwa ◽  
Michael Kessler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Cells ◽  
Metastatic Tumor ◽  
Skeletal Metastases ◽  
Bone Morphology ◽  
3D Scaffolds ◽  
Β Receptor ◽  
2D And 3D

Patients with advanced skeletal metastases arising from primary cancers including breast, lung, and prostate suffer from extreme pain, bone loss, and frequent fractures. While the importance of interactions between bone and tumors is well-established, our understanding of complex cell–cell and cell–microenvironment interactions remains limited in part due to a lack of appropriate 3D bone models. To improve our understanding of the influence of bone morphometric properties on the regulation of tumor-induced bone disease (TIBD), we utilized bone-like 3D scaffolds in vitro and in vivo. Scaffolds were seeded with tumor cells, and changes in cell motility, proliferation, and gene expression were measured. Genes associated with TIBD significantly increased with increasing scaffold rigidity. Drug response differed when tumors were cultured in 3D compared to 2D. Inhibitors for Integrin β3 and TGF-β Receptor II significantly reduced bone-metastatic gene expression in 2D but not 3D, while treatment with the Gli antagonist GANT58 significantly reduced gene expression in both 2D and 3D. When tumor-seeded 3D scaffolds were implanted into mice, infiltration of myeloid progenitors changed in response to pore size and rigidity. This study demonstrates a versatile 3D model of bone used to study the influence of mechanical and morphometric properties of bone on TIBD.

scholarly journals Cancer-Associated Fibroblasts Modulate Transcriptional Signatures Involved in Proliferation, Differentiation and Metastasis in Head and Neck Squamous Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3361
Author(s):  
Emilia Wiechec ◽  
Mustafa Magan ◽  
Natasa Matic ◽  
Anna Ansell-Schultz ◽  
Matti Kankainen ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
In Vitro Models ◽  
Cancer Associated Fibroblasts ◽  
Mesenchymal Transition ◽  
2D And 3D

Cancer-associated fibroblasts (CAFs) are known to increase tumor growth and to stimulate invasion and metastasis. Increasing evidence suggests that CAFs mediate response to various treatments. HNSCC cell lines were co-cultured with their patient-matched CAFs in 2D and 3D in vitro models, and the tumor cell gene expression profiles were investigated by cDNA microarray and qRT-PCR. The mRNA expression of eight candidate genes was examined in tumor biopsies from 32 HNSCC patients and in five biopsies from normal oral tissue. Differences in overall survival (OS) were tested with Kaplan–Meier long-rank analysis. Thirteen protein coding genes were found to be differentially expressed in tumor cells co-cultured with CAFs in 2D and 81 in 3D when compared to tumor cells cultured without CAFs. Six of these genes were upregulated both in 2D and 3D (POSTN, GREM1, BGN, COL1A2, COL6A3, and COL1A1). Moreover, two genes upregulated in 3D, MMP9 and FMOD, were significantly associated with the OS. In conclusion, we demonstrated in vitro that CAF-derived signals alter the tumor cell expression of multiple genes, several of which are associated with differentiation, epithelial-to-mesenchymal transition (EMT) phenotype, and metastasis. Moreover, six of the most highly upregulated genes were found to be overexpressed in tumor tissue compared to normal tissue.

In vitro chemosensitivity of freshly explanted tumor cells to pemetrexed is correlated with target gene expression

2007 ◽  
Vol 25 (5) ◽  
pp. 417-423 ◽  
Author(s):  
Axel-Rainer Hanauske ◽  
Ulrike Eismann ◽  
Olaf Oberschmidt ◽  
Heike Pospisil ◽  
Steve Hoffmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Cells ◽  
Target Gene ◽  
Target Gene Expression ◽  
In Vitro Chemosensitivity

scholarly journals In Vitro Assessment of Efficacy and Cytotoxicity of Prunus africana Extracts on Prostate Cancer C4-2 Cells

2021 ◽  
Author(s):  
Peace C. Asuzu ◽  
Alberta N.A. Aryee ◽  
Nicholas Trompeter ◽  
Yasmin Mann ◽  
Samuel A. Besong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lncap Cells ◽  
Leaf Extracts ◽  
Cytotoxic Effects ◽  
Prunus Africana ◽  
Plant Parts ◽  
Dependent Inhibition ◽  
Hormone Sensitive ◽  
In Vitro Assessment

AbstractPhenolic compounds are products of secondary plant metabolism known for their biological activity including their antimicrobial, antioxidant, analgesic, stimulant, anti- carcinogenic, and aphrodisiac properties. The main objective of this study was to assess the potency/cytotoxic effects of Prunus africana extracts on prostate cancer cells in vitro. Using different concentrations of P. africana extracts, prostate cancer C4-2 cells, a hormonally insensitive subline of LNCaP cells, were treated in a proliferation assay. A concentration dependent inhibition of cell growth in cells treated with P. africana bark and root extracts was present from days 1 through 3 of incubation, with the methanol extract of the bark showing the strongest effect. Compared to other plant parts, leaf extracts were significantly less cytotoxic at the same concentrations. As C4-2 cells are hormonally insensitive and designed to mimic advanced prostate cancer, crude extracts of P. africana are a possible treatment option, not only for hormone sensitive prostate cancer, but also advanced, hormonally insensitive prostate cancer.

Effect of lipopeptide structure on gene delivery system properties: Evaluation in 2D and 3D in vitro models

2018 ◽  
Vol 167 ◽  
pp. 328-336 ◽  
Author(s):  
O.O. Koloskova ◽  
A.M. Gileva ◽  
M.G. Drozdova ◽  
M.V. Grechihina ◽  
N.E. Suzina ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Delivery System ◽  
In Vitro Models ◽  
Gene Delivery System ◽  
System Properties ◽  
2D And 3D

The Activity of Urolithin A and M4 Valerolactone, Colonic Microbiota Metabolites of Polyphenols, in a Prostate Cancer In Vitro Model

Planta Medica ◽  
2018 ◽  
Vol 85 (02) ◽  
pp. 118-125 ◽  
Author(s):  
Iwona Stanisławska ◽  
Sebastian Granica ◽  
Jakub Piwowarski ◽  
Joanna Szawkało ◽  
Krzysztof Wiązecki ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
In Vitro Model ◽  
Specific Antigen ◽  
Lncap Cells ◽  
Isobolographic Analysis ◽  
Human System ◽  
Urolithin A ◽  
Vitro Model ◽  
Induced Apoptosis

AbstractThe gut microbiota-derived metabolites of ellagitannins and green tea catechins, urolithin A (uroA) and 5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone (M4), respectively, are among the main compounds absorbed into human system after ingestion of these polyphenols. The aim of this study was to establish the effects of M4, uroA, and their combinations on LNCaP cells, an androgen dependent prostate cancer in vitro model.. The LNCaP cells were incubated with increasing concentrations of tested metabolites. The cell proliferation was determined by measurement of DNA-bisbenzimide H 33 258 complexes fluorescence. The isobolographic analysis was used to establish the type of interaction between metabolites. The apoptosis, androgen receptor (AR) localization, and phosphorylation of Akt kinase were measured by flow cytometry. Prostate-specific antigen (PSA) secretion was determined by ELISA. M4 showed modest antiproliferative activity in LNCaP cells (IC50 = 117 µM; CI: 81 – 154). UroA decreased proliferation (IC50 = 32.7 µM; CI: 24.3 – 41.1) and induced apoptosis of LNCaP cells. The mixture of M4 with uroA had synergistic antiproliferative effect. Moreover, M4 potentiated inhibition of PSA secretion and enhanced retention of AR in cytoplasm caused by uroA. Interestingly, uroA increased levels of pSer473 Akt in LNCaP cells. These results show that colonic metabolites may contribute to chemoprevention of prostate cancer by varied polyphenol-rich diet or composite polyphenol preparations.

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