Curcumin synergistically enhances the efficacy of gemcitabine against gemcitabine-resistant cholangiocarcinoma via LAT2/glutamine pathway
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PROVIDER: PRJEB76114 | ENA |
REPOSITORIES: ENA
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Project description:Cholangiocarcinoma (CCA) is often diagnosed late, leading to incomplete tumor removal, drug resistance and reduced chemotherapy efficacy. Curcumin has the potential for anti-cancer activity through various therapeutic properties and can improve the efficacy of chemotherapy. We aimed to investigate the synergistic effect of a combination of curcumin and gemcitabine against CCA, targeting the LAT2/glutamine pathway. This combination synergistically suppressed proliferation in gemcitabine-resistant CCA cells (KKU-213BGemR). It also resulted in a remarkable degree of CCA cell apoptosis and cell cycle arrest, characterized by a high proportion of cells in the S and G2/M phases. Knockdown of SLC7A8 decreased the expressions of glutaminase and glutamine synthetase, resulting in inhibited cell proliferation and sensitized CCA cells to gemcitabine treatment. Moreover, in vivo experiments showed that a combination curcumin and gemcitabine significantly reduced tumor size, tumor growth rate and LAT2 expression in a gemcitabine-resistant CCA xenograft mouse model. Suppression of tumor progression in an orthotopic CCA hamster model provided strong support for clinical application. In conclusion, curcumin synergistically enhances gemcitabine efficacy against gemcitabine-resistant CCA by induction of apoptosis, partly via inhibiting LAT2/glutamine pathway. This approach may be an alternative strategy for the treatment of gemcitabine-resistant in CCA patients.
| S-EPMC11239878 | biostudies-literature
Project description:Cholangiocarcinoma (CCA) poses a significant health challenge, especially in Asian countries. Late-stage diagnoses limit the availability of curative surgical options, underscoring the crucial role of chemotherapy. However, drug resistance presents a formidable obstacle, resulting in recurrent tumors. Despite the revolutionary impact of proteomics on cancer research, the exploration of drug-resistant mechanisms in CCA remains unexplored. In this study, we established 5-fluorouracil (5-FU)- and gemcitabine-resistant CCA cell lines, KKU-213FR and KKU-213GR, derived from the KKU-213A parental line. These cell lines exhibited robust drug resistance, heightened migration, and invasion capabilities.
2024-07-03 | PXD049309 | JPOST Repository
Project description:Establishment and characterization of a new intrahepatic cholangiocarcinoma cell line resistant to gemcitabine
| PRJNA477325 | ENA
Project description:Intrahepatic cholangiocarcinoma (ICC) is one of the most lethal liver cancers. The late diagnosis as well as the resistance to chemotherapy concurred to the scarce outfit of this malignancy. Even the improvement of the knowledge and, as consequence, of the broad spectrum of alternative therapies available (i.e. targeted, immune checkpoint inhibitors), the survival and the quality of life remain poor. The phenomenon of resistance is not still clear. Here, we established one gemcitabine, GEM, (the standard therapy in ICC) resistant cell line, named MTCHC01R1.5, obtained by a gradual exposure to GEM for 9 months (up to 1.5 µM) of the sensible counterpart MT-CHC01. We biologically and molecularly characterized this cell line comparing its behavior with its parental cell line. The drug resistance is irreversible, even if cells are treated with high doses of GEM. They grew slowly, both in vitro and in vivo, and no differences are highlighted in terms of migration and invasion. GEM resistance promoted a multi drug resistance development, but the drug prediction analysis showed that paclitaxel and doxycycline could overcome GEM resistance, as confirmed by cell viability assay. There is a global enrichment of up-regulated genes involved in the regulation of cell cycle and in DNA related process. The down-regulated genes are involved in response to stimuli, and xenobiotic metabolism, and angiogenesis. A deregulation of more than 20 genes related to drug resistance and epithelial to mesenchymal transition (EMT) was found. The trend in expression of 9 genes related to resistance is confirmed in a primary cell culture. In conclusion, we characterized a new Italian GEM resistance ICC model which could be exploited either to study the mechanism of resistance or to explore new therapies.
2019-05-30 | GSE116118 | GEO
Project description:CCLP cholangiocarcinoma cells were transfected with CTRL inhibitor or MIR1249 inhibitor for 48 hours and treated with DMSO or chemotherapy (cisplatin and gemcitabine) for 48 hours before being collected and analysed for gene expression
2022-06-06 | GSE132328 | GEO
Project description:We examined the microarray-based expression profiles of the cells to identify genes associated with gemcitabine resistance Using a set of parental and gemcitabine resistant cell line, MKN28 and RMKN28, we studied mRNA transcription levels by microarray analysis to see if there are any of the key molecules for development of acquisition of the GEM resistance.
2015-05-01 | E-GEOD-58118 | biostudies-arrayexpress
Project description:KBwt is a KB parental cell KBHURs is a hydroxyurea resistant KB clone KBGem is a gemcitabine resistant KB clone Keywords: HU95 V2
2007-08-30 | GSE3344 | GEO
Project description:Gallbladder cancer (GBC) has few therapeutic options, being gemcitabine the first-line chemotherapeutic drug. However, this treatment shows poor clinical outcomes on patients. The acquired resistance phenomenon during of the treatment is one of the main factors that leads to insufficient therapeutic effects, and the molecular mechanisms carried out by tumor cells against gemcitabine are still poorly understood. First, we established a GBC cell line with acquired resistance to gemcitabine (NOZ GemR) from parental cell line (NOZ). After, we used microarray hybridization in NOZ and NOZ GemR to characterize their transcriptional profile to identify differentially expressed genes and/or molecular pathways involved chemoresistant cell phenotype.
2022-07-21 | GSE208659 | GEO
Project description:Gallbladder cancer (GBC) has few therapeutic options, being gemcitabine the first-line chemotherapeutic drug. However, this treatment shows poor clinical outcomes on patients. The acquired resistance phenomenon during of the treatment is one of the main factors that leads to insufficient therapeutic effects, and the molecular mechanisms used by tumor cells against gemcitabine are still poorly understood. First, we established a GBC cell line with acquired resistance to gemcitabine (TGBC1 GemR) from parental cell line (TGBC1). After, we used microarray hybridization in TGBC1 and TGBC1 GemR to characterize their transcriptional profile to identify differentially expressed genes and/or molecular pathways involved chemoresistant cell phenotype.
2022-07-21 | GSE208660 | GEO
Project description:Purpose: Chemotherapy is pivotal in the multimodal treatment of pancreatic cancer patients. In recent years, technical advances have developed experimental methods that unveiled a high degree of inter- and intratumoral heterogeneity in pancreatic cancer. We hypothesized that intratumoral heterogeneity (ITH) impacts response to gemcitabine treatment and demands specific targeting of resistant subclones. Experimental Design: We addressed the effect of ITH on response to gemcitabine treatment using single cell-derived cell lines (SCDCL) from the classical-like cell line BxPC3 and the basal-like cell line Panc-1 which were analyzed by mRNA-seq and mass spectrometry. Results: Individual SCDCLs of the parental tumor cell populations of BxPC3 and Panc-1 showed considerable heterogeneity in response to gemcitabine. Unsupervised principal component analysis (PCA) including the 1,000 most variably expressed genes showed a clustering of the SCDCLs according to their respective sensitivity to gemcitabine treatment for BxPC3, while this clustering was less clear for Panc-1. In BxPC3 SCDCLs, enriched signaling pathways EMT, TNF signaling via NfKB, and IL2STAT5 signaling correlated with more resistant behavior to gemcitabine. In Panc-1 SCDCLs MYC targets V1 and V2 as well as E2F targets were associated with stronger resistance to gemcitabine. Feature extraction of proteomes again identified less proteins whose expression was associated with the response of individual SCDCLs in Panc-1 compared to BxPC3. Based on molecular profiles, we could show that the gemcitabine-resistant SCDCLs of both BxPC3 and Panc-1 are more sensitive to the BET inhibitor JQ1 compared to the respective gemcitabine-sensitive SCDCLs. Conclusions: Our model system of SCDCLs identified gemcitabine-resistant subclones within a parental tumor population and provides evidence for the critical role of ITH for treatment response in pancreatic cancer. Through molecular profiling, we identified specific signaling pathways and protein signatures that might help to explain the differential response to treatment among clones. We exploited these molecular differences for an improved and more targeted therapy of resistant subclones of a heterogeneous tumor.
2023-09-19 | PXD042256 | Pride