Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency II
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE205556 | GEO | 2022/10/31
REPOSITORIES: GEO
Similar Datasets
Project description:We analysed differences in gene expression upon treatment of MSD patient fibroblast lines with either tazarotene or adapalene and DMSO control (untreated condition)
2022-11-04 | GSE205555 | GEO
Project description:Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency
| PRJNA846323 | ENA
Project description:Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency II
| PRJNA846322 | ENA
Project description:Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Differentiation can attenuate or block tumor growth; thus, phenotypic screenings were performed to search for drugs inducing differentiational morphological changes in mesenchymal recurrent GBM, a temozolomide (TMZ)-resistant brain cancer. Bexarotene, a selective retinoid X receptor agonist, showed strong inhibition of neurospheroidal colony formation and migration of cultured GBM stem cells. Bexarotene decreased nestin expression and significantly increased GFAP expression. Gene expression changes by bexarotene and all-trans retinoic acid (ATRA), a well-known differentiation inducer, were compared. Both drugs largely altered the gene expression pattern into a tumor-ameliorating direction. These drugs increased the gene expression levels of Krüppel-like factor 9 (KLF9), regulator of G-protein signaling 4 (RGS4), growth differentiation factor 15 (GDF15), angiopoietin-like protein 4 (ANGPTL4), and lowered the level of chemokine receptor type 4 (CXCR4). Both drugs also induced a potential oncogene, transglutaminase 2 (TG2), but the fold-change induced by bexarotene was considerably lesser than that by ATRA. Consistently, the TG2 activity in GBM was elevated several folds by ATRA. Because TG2 upregulation is correlated with tumor transformation and resistance, it is important to control its overexpression. Bexarotene does not upregulate TG2 as much as ATRA, and bexarotene showed in vivo tumoricidal effects in a GBM xenograft mouse model. Thus, these findings strongly suggest that bexarotene is more beneficial than ATRA and should be considered as a differentiation therapeutic agent for mesenchymal GBM.
2014-12-31 | GSE61002 | GEO
Project description:Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine-generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent sulfatase activities and, as a result, clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are limited and mostly palliative. We performed a screen of FDA-approved drugs using immortalized MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of primary MSD fibroblasts with tazarotene and bexarotene, two retinoids, led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose- and time-dependent manner, reduced glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients.
| S-EPMC9994482 | biostudies-literature
Project description:Multiple Sulfatase Deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine-generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced sulfatase activities and clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are mostly palliative. We performed a screen of FDA-approved drugs using immortalised MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of MSD fibroblasts with tazarotene and bexarotene led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose- and time-dependent manner, glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients.
| S-SCDT-10_15252-EMMM_202114837 | biostudies-other
Project description:Acquired drug resistance represents a major challenge in chemo-therapy treatment for various types of cancers. We have found that the retinoid X receptorâselective agonist bexarotene (LGD1069, Targretin) was efficacious in treating chemo-resistant cancer cells. The goal of this microarray study was to understand the mechanism of bexaroteneâs role in overcoming acquired drug resistance using human breast cancer cells MDA-MB-231 as a model system and paclitaxel as model compound. After MDA-MB-231 cells were repeatedly treated with paclitaxel for 8 cycles with each cycle including a 3-day treatment with 30 nM paclitaxel and followed by a 7-day exposure to control medium, MDA cells resistant to paclitaxel were developed and their growth was no longer inhibited by paclitaxel treatment. Those MDA cells with acquired drug resistance, when treated with paclitaxel and bexarotene in combination, could regain their sensitivity and their growth were again inhibited. Therefore, RNA samples from parental MDA-MB-231 cells, paclitaxel-resistant MDA cells treated with vehicle, paclitaxel alone or in combination with bexarotene, were used for perform global gene expression profiling with Affymetrix HG-U133A gene chips. Keywords: Drug Treatment MDA-MB-231 cells were exposed to regimens on a 10-day cycle: a 3-day treatment with 30 nM paclitaxel and followed by a 7-day exposure to control medium. Paclitaxel resistant MDA-MB-231 cells (MDA-PR) were established within 8 cycles of such treatment (80 days). These MDA-PR cells were then treated with vehicle control, paclitaxel along, or the combination of 30 nM paclitaxel ( 3 days on and 7 days off) and 1 µM Targretin (10 days on) in a new 10-day cycle for 3 months. Thus, there are four treatment groups, parent MDA cells, MDA-PR, MDA-PR treated with paclitaxel, MDA-PR treated with paclitaxel and bexarotene, and each group had four biological replicates.
2011-07-18 | E-GEOD-12791 | biostudies-arrayexpress
Project description:Resistance of Calu3 NSCLC cells to the cytotoxic nucleoside analog gemcitabine (2',2'-difluorodeoxycytidine) can be prevented as well as reversed by the rexinoid X receptor selective agonist bexarotene. This study was designed to investigate the changes in gene expression associated with gemcitabine resistance and its reversal by bexarotene. In addition to the parental Calu3 cells and the 10 cycles of treatment of the gemcitabine resistant Calu3 cells with vehicle or bexarotene, analogous treatment paradigms with gemcitabine alone as well as the combination of both compounds have been included as controls. (However, it has to be noted that in the combination treatment, cells that were re-sensitized by bexarotene have largely been removed from the culture before harvest due to the cytotoxic activity of gemcitabine.) Keywords: cell type comparison, compound effects
2007-01-31 | GSE6914 | GEO
Project description:mRNA expression in two different cell lines (DEV and G401) and two conditions (CLOFILIUM and DMSO) were assessed using the Illumina HiSeq2500 plateform in order to detect genes that are differentially expressed in CLOFILIUM condition compared to control (DMSO)
2017-11-02 | GSE102467 | GEO
Project description:Acquired drug resistance represents a major challenge in chemo-therapy treatment for various types of cancers. We have found that the retinoid X receptor–selective agonist bexarotene (LGD1069, Targretin) was efficacious in treating chemo-resistant cancer cells. The goal of this microarray study was to understand the mechanism of bexarotene’s role in overcoming acquired drug resistance using human breast cancer cells MDA-MB-231 as a model system and paclitaxel as model compound. After MDA-MB-231 cells were repeatedly treated with paclitaxel for 8 cycles with each cycle including a 3-day treatment with 30 nM paclitaxel and followed by a 7-day exposure to control medium, MDA cells resistant to paclitaxel were developed and their growth was no longer inhibited by paclitaxel treatment. Those MDA cells with acquired drug resistance, when treated with paclitaxel and bexarotene in combination, could regain their sensitivity and their growth were again inhibited. Therefore, RNA samples from parental MDA-MB-231 cells, paclitaxel-resistant MDA cells treated with vehicle, paclitaxel alone or in combination with bexarotene, were used for perform global gene expression profiling with Affymetrix HG-U133A gene chips. Keywords: Drug Treatment
2011-07-19 | GSE12791 | GEO