Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA117795 | ENA |
REPOSITORIES: ENA
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Project description:The quinoline-3-carboxamide ABR-215050 (Tasquinimod (INN)), exhibits anti-tumor activity via inhibition of tumor angiogenesis in human and rodent tumors. To further explore the mode of action of ABR-215050, in vivo experiments with gene microarray analysis were performed using samples of LNCaP prostate tumors excised from nude mice exposed to ABR-215050 for 24h at 10 mg/kg(ad.lib.). The array data were validated by real-time PCR (sqRT-PCR), as well as by protein expression experiments. Among several significant differentially expressed gene after exposure to ABR-215050, were cytokine receptor CXCR4, cytochrome P450 1A1 (CYP1A1), thrombospondin-1 (THBS1) and Lysyloxidase preprotein (LOX). To further explore the mode of action of ABR-215050, in vitro experiments with gene microarray analysis were performed using LNCaP prostate tumor cells. The array data were validated by real-time PCR (sqRT-PCR), as well as by protein expression experiments. One of the most significant differentially expressed genes after exposure to ABR-215050, was thrombospondin-1 (THBS1). 2-color treatment vs. control microarray experiment comprising four biological replicates. Each biological replicate was hybridized with dye-swap; resulting in eight hybridizations for each dataset (in vitro and in vivo), for a total of 16 hybridizations.
2011-03-01 | E-GEOD-17031 | biostudies-arrayexpress
Project description:The quinoline-3-carboxamide ABR-215050 (Tasquinimod (INN)), exhibits anti-tumor activity via inhibition of tumor angiogenesis in human and rodent tumors. To further explore the mode of action of ABR-215050, in vivo experiments with gene microarray analysis were performed using samples of LNCaP prostate tumors excised from nude mice exposed to ABR-215050 for 24h at 10 mg/kg(ad.lib.). The array data were validated by real-time PCR (sqRT-PCR), as well as by protein expression experiments. Among several significant differentially expressed gene after exposure to ABR-215050, were cytokine receptor CXCR4, cytochrome P450 1A1 (CYP1A1), thrombospondin-1 (THBS1) and Lysyloxidase preprotein (LOX). To further explore the mode of action of ABR-215050, in vitro experiments with gene microarray analysis were performed using LNCaP prostate tumor cells. The array data were validated by real-time PCR (sqRT-PCR), as well as by protein expression experiments. One of the most significant differentially expressed genes after exposure to ABR-215050, was thrombospondin-1 (THBS1).
2011-03-01 | GSE17031 | GEO
Project description:The quinoline-3-carboxamide, Tasquinimod, is orally active as a maintenance therapy with an on-target mechanism-of-action via allosteric binding to HDAC4. This prevents formation of the HDAC4/NCoR1/HDAC3 complex, disrupting HIF-1α transcriptional activation and repressing MEF-2 target genes needed for adaptive survival signaling in the compromised tumor microenvironment (TME). In phase 3 clinical testing against metastatic castration-resistant prostate cancer (mCRPC), Tasquinimod (1 mg/day) increased time-to-progression, but not overall survival. Here, we document that, on this regimen, blood levels are 10-fold lower than the optimal concentration (≥2 μM) needed for anti-cancer activity, suggesting higher daily doses are needed. Unfortunately, we also demonstrate that Tasquinimod is an aryl hydrocarbon receptor (AHR) agonist, which binds with an EC50 of 1 μM to produce unwanted off-target side effects. Therefore, we screened a library of Tasquinimod analogs to maximize on-target vs. off-target activity. Using this approach, we identified ESATA-20, which has ~10-fold lower AHR agonism and >5-fold greater potency against prostate cancer patient-derived xenografts. This increased therapeutic index nominates ESATA-20 as a lead candidate for clinical development as an orally active 3rd generation quinoline-3-carboxamide analog that retains its on-target ability to disrupt HDAC4/HIF-1α/MEF-2-dependent adaptive survival signaling in the compromised TME found in mCRPC.
2023-08-11 | GSE211375 | GEO
Project description:Lineage plasticity is increasingly recognized as a resistance mechanism to androgen receptor (AR) inhibition in prostate cancer. Neuroendocrine prostate cancer (NEPC) is the most lethal form of lineage plasticity in prostate cancer. BET bromodomain inhibitors (BETi) previously were shown to block genes associated with lineage plasticity. Extensive rewiring of DNA methylation is also associated with NEPC tumors. We sought to determine whether combined BET protein and DNA methyltransferase inhibition (DNMTi) would result in greater anti-tumor activity than single agent treatments alone. To test this, we treated NEPC cell line models with 500nM ZEN (BETi), 100nM dAZA (DNMTi), or the combination daily for 72hrs. We also tested the BETi + DNMTi combination in vivo using an NEPC PDX (LTL331R) with 50mg/kg ZEN and 0.8mg/kg dAZA. Combined BETi and DNMTi was more effective than single agent treatment in suppressing growth in NEPC models compared to single agent treatments. To identify the DNA methylation changes underlying the superior viability effect of the combo treatment, we peformed enhanced reduced representation bisulfite sequencing (ERRBS) on treated cells.
2026-06-22 | GSE311321 | GEO
Project description:Castration-resistant prostate cancer (CRPC) is an incurable form of prostate cancer (PC) and a major therapeutic challenge. Here, we show that the natural compound, atraric acid (AA), inhibits besides the androgen receptor (AR) those AR-mutants that confer therapy resistance to AR-antagonists indicating a different mode of AR-antagonism. AA induces cellular senescence and inhibits intratumoral angiogenesis and CRPC tumour growth in treated xenograft mice. RNA-seq reveals an upregulated angiogenic transcriptional pathway by androgen. In line with this, conditioned medium from CRPC cells induces angiogenesis in two in vitro models using primary human endothelial cells. By employing immune arrays and mass-spec analyses, we found that androgens induced secretion of pro-angiogenic factors pinpointing to angiopoeitin2 (ANGPT2). The senescence-associated secretory phenotype revealed reduced ANGPT2 secretion by AA. Accordingly, immune-depletion of ANGPT2 or blocking ANGPT2-receptors inhibits angiogenesis. Our data propose AA as potential anti-PCa compound and ANGPT2 pathway as novel therapeutic target for CRPC.
2021-08-31 | GSE151492 | GEO
Project description:Plasma proteomic profiles of small cell lung cancer patients treated with immune checkpoint inhibitors combined with anti-angiogenic therapy as second- or further-line treatment
2025-02-25 | PXD061159 |
Project description:Lineage plasticity is increasingly recognized as a resistance mechanism to androgen receptor (AR) inhibition in prostate cancer. Neuroendocrine prostate cancer (NEPC) is the most lethal form of lineage plasticity in prostate cancer. BET bromodomain inhibitors (BETi) previously were shown to block genes associated with lineage plasticity. Extensive rewiring of DNA methylation is also associated with NEPC tumors. We sought to determine whether combined BET protein and DNA methyltransferase inhibition (DNMTi) would result in greater anti-tumor activity than single agent treatments alone. To test this, we treated NEPC cell line models with 500nM ZEN (BETi), 100nM dAZA (DNMTi), or the combination daily for 72hrs. We also tested the BETi + DNMTi combination in vivo using an NEPC PDX (LTL331R) with 50mg/kg ZEN and 0.8mg/kg dAZA. Combined BETi and DNMTi was more effective than single agent treatment in suppressing growth in NEPC models compared to single agent treatments. To identify the gene expression changes underlying the superior viability effect of the combo treatment, we peformed RNAseq on treated cells. We also performed RNAseq on a PDX model that reliably transitions from adenocarcinoma (LTL331) to NEPC (LTL331R) in order to uncover the gene expression changes associated with NEPC lineage plasticity and to determine whether BETi and/or DNMTi reverses these gene expression changes.
2026-06-22 | GSE309034 | GEO
Project description:Background: Cantharidin, an active constituent of mylabris, is believed to have anti-tumor activity. Cantharidin selectively inhibit protein phosphatase 2A (PP2A), a repressor of oncogenic kinase pathways (ERK, JNK, NF-κB, and PKC). Cantharidin represses the growth and metastasis of pancreatic cancer cells in vitro. In the present study, we investigated the effects of cantharidin on pancreatic cancer xenografts in vivo. Methods: Cells stably expressing luciferase were used to establish xenograft models. Xenograft growth was evaluated by living imaging. Gene expression was determined using a microarray, real-time PCR, a RayBiotech antibody array, and the Milliplex assay. Results: Surprisingly, cantharidin significantly accelerated xenograft growth. Living imaging showed a rapid distribution of D-luciferin in cantharidin-treated xenografts, suggesting a rich blood supply. Immunohistochemistry confirmed increased angiogenesis. Microarray and antibody array identified upregulated pro-angiogenic and downregulated anti-angiogenic factors. The Milliplex assay suggested elevated secretion of IL-6, IL-8, TNF-α, and VEGF. ERK, JNK, NF-κB, and PKC pathway inhibitors attenuated the cantharidin-induced changes to pro-angiogenic gene expression. PKC pathway-inhibiting tamoxifen or antiangiogenic therapeutics, including Ginsenoside Rg3, bevacizumab, Apatinib, and Endostar antagonized the pro-angiogenic effect of cantharidin or its derivatives. These regimens presented remarkable synergistic antitumor effects in vivo. Conclusion: Although cantharidin presents anti-tumor effects in vitro and has been applied in clinical practice, we revealed an unfavorable pro-angiogenic side effect. We recommend that the clinical application of cantharidin should be performed on the premise of anti-vascularization therapy.
2018-12-06 | GSE114040 | GEO
Project description:Cervical cancer is still the leading cause of cancer mortality worldwide even after introduction of vaccine against Human papillomavirus (HPV), due to low vaccine coverage, especially in the developing world. Cervical cancer is primarily treated by Chemo/Radiotherapy, depending on the disease stage, with Carboplatin/Cisplatin-based drug regime. These drugs being non-specific, target rapidly dividing cells, including normal cells, so safer options are needed for lower off-target toxicity. Natural products offer an attractive option compared to synthetic drugs due to their well-established safety profile and capacity to target multiple oncogenic hallmarks of cancer like inflammation, angiogenesis, etc. In the current study, we investigated the effect of Bergenin (C-glycoside of 4-O-methylgallic acid), a natural polyphenol compound that is isolated from medicinal plants such as Bergenia crassifolia, Caesalpinia digyna, and Flueggea leucopyrus . Bergenin has been shown to have anti-inflammatory, anti-ulcerogenic, and wound healing properties but its anticancer potential has been realized only recently. We performed a proteomic analysis of cervical carcinoma cells treated with bergenin and found it to influence multiple hallmarks of cancers, including apoptosis, angiogenesis, and tumor suppressor proteins. It was also involved in many different cellular processes unrelated to cancer, as shown by our proteomic analysis. Further analysis showed bergenin to be a potent -angiogenic agent by reducing key angiogenic proteins like Galectin 3 and MMP-9 (Matrix Metalloprotease 9) in cervical carcinoma cells. Further understanding of this interaction was carried out using molecular docking analysis, which indicated MMP-9 has more affinity for bergenin as compared to Galectin-3. Cumulatively, our data provide novel insight into the anti-angiogenic mechanism of bergenin in cervical carcinoma cells by modulation of multiple angiogenic proteins like Galectin-3 and MMP-9 which warrant its further development as an anticancer agent in cervical cancer.
2024-03-04 | PXD043359 | Pride
Project description:Resistance formation is one of the major hurdles in cancer therapy. Metronomic anti-angiogenic treatment of xenografted prostate cancer tumors in SCID mice with cyclophosphamide (CPA) results in the appearance of resistant tumors. To investigate the complex molecular changes occurring during resistance formation, we performed a comprehensive gene expression analysis of the resistant tumors in vivo. We observed a multitude of differentially expressed genes, e.g., PASD1, ANXA3, NTS or PLAT, when comparing resistant to in vivo passaged tumor samples. Furthermore, tumor cells from in vivo and in vitro conditions showed a significant difference in target gene expression. We assigned the differentially expressed genes to functional pathways like axon guidance, steroid biosynthesis and complement and coagulation cascades. Most of the genes were involved in anti-coagulation, indicating its possible importance. Upregulation of anti-coagulatory ANXA3 and PLAT and downregulation of PLAT inhibitor SERPINA were validated by qPCR. In contrast, coagulation factor F3 was upregulated, accompanied by the expression of an altered gene product. These findings give insights into the resistance mechanisms of metronomical CPA treatment suggesting an important role of anti-coagulation in resistance formation. 4 cell lines * 2 treatments * 4 replicates = 32 arrays. One sample (C3-T) was identified as an outlier and was omitted from further analysis; it is not included here.
2013-01-23 | E-GEOD-42913 | biostudies-arrayexpress