Comparative study of effect of thalidomide, lenalidomide and pomalidomide on Human umbilical vein endothelial cells (HUVECs)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE118979 | GEO | 2021/08/31
REPOSITORIES: GEO
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Project description:Comparative study of effect of thalidomide, lenalidomide and pomalidomide on Human umbilical vein endothelial cells (HUVECs)
| PRJNA487600 | ENA
Project description:We synthesized novel fluorescent thalidomide analogs (2,6-dialkylphenyl-4/5-amino-substituted-5,6,7-trifluorophthalimides) that localize specifically to lipid droplets. By using affinity chromatography interacting proteins were identified: Rab7, Rab10, Rab11, Sec22b, sorting nexin 2, calnexin, protein disulfide isomerase, GRP78, GRP94 among others that are involved in vesicular transport and ER stress response. Amino-trifluoro-phthalimides exerted potent anticancer activities in vitro on different cell lines including melanoma, leukemia, hepatocellular carcinoma, glioblastoma. They are non-toxic to adult animals up-to 1 g/kg but are highly teratogenic to zebrafish embryos at micromolar concentrations resulting defects in developing muscle. The analogs resulted in calcium release from the endoplasmic reticulum (ER), induction of reactive oxygen species (ROS), ER stress and finally apoptosis. Gene expression analysis confirmed the induction of ER stress-mediated apoptosis pathway components, such as growth arrest- and DNA damage-inducible gene 153 (GADD153), ATF3, Luman/CREB3 recruitment factor (LRF) and the ER-associated degradation-related gene HERPUD1. Tumor suppressors, P53, LATS2 and ING3 were also up-regulated in various cell lines after drug treatment. Exogenous docosahexaenoic acid or eicosapentaenoic acid induced calcium release and ROS and synergized with the analogs in vitro, while oleic acid had no such an effect. Different antioxidants partially, intracellular calcium chelator almost completely diminished ROS production. Amino-phthalimides down-regulated the expression of CCL2, which is implicated in tumor metastasis and angiogenesis. Because of the anticancer, anti-angiogenic action and the wide range of applicability of the immunomodulatory drugs, lipid droplet-binding members of this family could represent a new class of agents by affecting ER-membrane integrity and perturbations of ER homeostasis. 4 replica, 2 dye-swap
2010-02-22 | E-GEOD-14945 | biostudies-arrayexpress
Project description:The scope of this study is to understand effect of microgravity on HUVECs (Human Umbilical vein Endothelial cells) and comparative analysis with respect to control group.
2020-08-11 | GSE80292 | GEO
Project description:We synthesized novel fluorescent thalidomide analogs (2,6-dialkylphenyl-4/5-amino-substituted-5,6,7-trifluorophthalimides) that localize specifically to lipid droplets. By using affinity chromatography interacting proteins were identified: Rab7, Rab10, Rab11, Sec22b, sorting nexin 2, calnexin, protein disulfide isomerase, GRP78, GRP94 among others that are involved in vesicular transport and ER stress response. Amino-trifluoro-phthalimides exerted potent anticancer activities in vitro on different cell lines including melanoma, leukemia, hepatocellular carcinoma, glioblastoma. They are non-toxic to adult animals up-to 1 g/kg but are highly teratogenic to zebrafish embryos at micromolar concentrations resulting defects in developing muscle. The analogs resulted in calcium release from the endoplasmic reticulum (ER), induction of reactive oxygen species (ROS), ER stress and finally apoptosis. Gene expression analysis confirmed the induction of ER stress-mediated apoptosis pathway components, such as growth arrest- and DNA damage-inducible gene 153 (GADD153), ATF3, Luman/CREB3 recruitment factor (LRF) and the ER-associated degradation-related gene HERPUD1. Tumor suppressors, P53, LATS2 and ING3 were also up-regulated in various cell lines after drug treatment. Exogenous docosahexaenoic acid or eicosapentaenoic acid induced calcium release and ROS and synergized with the analogs in vitro, while oleic acid had no such an effect. Different antioxidants partially, intracellular calcium chelator almost completely diminished ROS production. Amino-phthalimides down-regulated the expression of CCL2, which is implicated in tumor metastasis and angiogenesis. Because of the anticancer, anti-angiogenic action and the wide range of applicability of the immunomodulatory drugs, lipid droplet-binding members of this family could represent a new class of agents by affecting ER-membrane integrity and perturbations of ER homeostasis.
2010-02-23 | GSE14945 | GEO
Project description:Endothelial cells (ECs) are phenotypically heterogeneous mainly due to their dynamic epigenetic status. VEGF, the best-known angiogenic factor, activates calcium-NFAT signalling following acute angiogenic gene transcription. Here, we evaluated the global mapping of VEGF-mediated dynamic transcriptional events with a particular focus on major histone-code profiles using ChIP-seq. Remarkably, the regulatory regions of angiogenic transcription factors exclusively acquired embryonic stem-like bivalent histone marks after the VEGF stimulus. Moreover, the newly discovered NFAT-associated epigenome modifier, PTIP in the COMPASS complex, directed gene transcription via MLL3/4-enrichment which overwhelmed the polycomb-brakes. The non-canonical polycomb1 variant, PRC1.3, specifically bound to and allowed the transactivation of PRC2-enriched bivalent angiogenic genes until conventional PRC1 association and gene silencing. Knockdown of these epigenome modifiers abrogated postnatal aberrant neovessel formation via selective inhibition of acute angiogenic bivalent gene transcription. Collectively, the reported dynamic epigenome landscape in ECs may support the development of advanced therapeutic strategies against various vasculopathies.
2021-10-06 | GSE159075 | GEO
Project description:Endothelial cells are critical for angiogenesis, and microRNAs plays important roles in this process. We investigated the regulatory role of microRNAs in endothelial cells of hepatocellular carcinoma (HCC) by examining the microRNA expression profile of human umbilical vein endothelial cells (HUVECs) in the absence or presence of human HCC cells, and identified miR-146a as the most highly up-regulated microRNA. Furthermore, we revealed that miR-146a promoted the expression of platelet-derived growth factor receptor (PDGFRA) in HUVECs, and this process was mediated by BRCA1. Overexpression of PDGFRA in the ECs of HCC tissues was associated with microvascular invasion, and predicted a poorer prognosis. These results suggest that MiR-146a plays a key role in regulating the angiogenic activity of ECs in HCC through miR-146a-BRCA1-PDGFRA pathway. MiR-146a may emerge as a potential anti-angiogenic target on ECs for HCC therapy.
2013-04-13 | GSE46022 | GEO
Project description:Endothelial cells are critical for angiogenesis, and microRNAs plays important roles in this process. We investigated the regulatory role of microRNAs in endothelial cells of hepatocellular carcinoma (HCC) by examining the microRNA expression profile of human umbilical vein endothelial cells (HUVECs) in the absence or presence of human HCC cells, and identified miR-146a as the most highly up-regulated microRNA. Furthermore, we revealed that miR-146a promoted the expression of platelet-derived growth factor receptor (PDGFRA) in HUVECs, and this process was mediated by BRCA1. Overexpression of PDGFRA in the ECs of HCC tissues was associated with microvascular invasion, and predicted a poorer prognosis. These results suggest that MiR-146a plays a key role in regulating the angiogenic activity of ECs in HCC through miR-146a-BRCA1-PDGFRA pathway. MiR-146a may emerge as a potential anti-angiogenic target on ECs for HCC therapy. We have employed whole genome OneArray to examine the genome expression changes of HUVECs overexpressing miR-146a.
2013-04-13 | E-GEOD-46022 | biostudies-arrayexpress
Project description:Thalidomide Exerts Distinct Molecular Antileukemic Effects and Combined Thalidomide/Fludarabine Therapy is Clinically Effective in High-Risk Chronic Lymphocytic Leukemia Background: Thalidomide represents a promising immunomodulatory drug that targets both leukemia cells and the tumor microenvironment. Methods: We treated chronic lymphocytic leukemia (CLL) patients with a combined thalidomide/fludarabine regimen and monitored cellular and molecular changes induced by thalidomide in-vivo prior to fludarabine treatment. Thalidomide was given daily (100mg p.o./day) and fludarabine was administered on days 7-11 (25 mg/m² i.v./day) within each 4-week cycle (maximum of 6 cycles). Twenty patients received thalidomide/fludarabine as first line therapy and 20 patients were previously treated. Unmutated IgVH mutation status was found in 36 cases and 13 had high-risk cytogenetic aberrations (deletion of 17p13 or 11q22-q23). Results: The overall response rate was 80% and 25% for untreated and previously treated patients, respectively. While thalidomide effectively reduced the number of CLL cells, the number of CD3 lymphocytes showed no significant change, but the number of CD4+CD25hiFOXP3+ T-regulatory cells was significantly decreased. Gene expression profiling revealed a thalidomide induced signature containing both targets known to play a role in immunomodulatory drug action as well as novel candidate genes. Conclusions: Combined thalidomide/fludarabine therapy demonstrated efficacy in high-risk CLL patients. Furthermore, our study provides novel biological insights into thalidomide effect, which might act by enhancing apoptosis of CLL cells and reducing Tregs, thereby enabling T-cell dependent anti-tumor effect.
2009-08-21 | GSE15913 | GEO
Project description:The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the anti-myeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to and putatively resistant to lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity, and a possible biomarker for the clinical assessment of anti-myeloma efficacy. We included 15 samples from multiple myeloma cell lines.
2011-09-30 | E-GEOD-31421 | biostudies-arrayexpress
Project description:The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the anti-myeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to and putatively resistant to lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity, and a possible biomarker for the clinical assessment of anti-myeloma efficacy. We included two isogenic MM1.S cell lines, which differ in the sensibiligy to lenalidomide. We included MM1.S and MM1.S res, which were sensitive and resistant to lenalidomide, respectively.
2011-09-30 | E-GEOD-31451 | biostudies-arrayexpress