Drug-drug interaction between metformin and sorafenib alters antitumor effect in hepatocellular carcinoma cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA682205 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is one of the leading causes of cancer-related deaths worldwide. The multi‐target inhibitor sorafenib is a first-line treatment for patients with advanced unresectable HCC. Recent clinical studies have evidenced that patients treated with sorafenib together with the anti-diabetic drug metformin have a survival disadvantage compared to patients receiving sorafenib only. Here, we examined whether a clinically relevant dose of metformin (50 mg/kg/d) could influence the antitumoral effects of sorafenib (15 mg/kg/d) in a subcutaneous xenograft model of human HCC growth using two different sequences of administration, i.e concomitant versus sequential dosing regimens. We observed that the administration of metformin six hours prior to sorafenib was significantly less effective in inhibiting tumor growth than concomitant administration of the two drugs. In vitro experiments confirmed that pretreatment of different human HCC cell lines with metformin reduced the effects of sorafenib on cell viability, proliferation and signaling. Transcriptomic analysis confirmed significant differences between xenografted tumors obtained under the concomitant and the sequential dosing regimens. Taken together, these observations call into question the benefit of parallel use of metformin and sorafenib in patients with advanced HCC and diabetes, as the interaction between the two drugs could ultimately compromise patient survival. To better characterize the molecular signatures driving the differential responses to concomitant and sequential biotherapies, we conducted a transcriptomic analysis on RNA extracted from tumor xenografts mice xenografed and treated with vehicle (control, n=3), metformin (50 mg/kg/day) combined to sorafenib (15 mg/kg/day) (concomitant schedule, n=3) or metformin (50 mg/kg/day) followed 6 hours later by sorafenib (15 mg/kg/day) (sequential schedule, n=3).
2020-12-03 | GSE162557 | GEO
Project description:Hepatocellular carcinoma (HCC) is frequently diagnosed in patients with late-stage disease who are ineligible for curative surgical therapies. Furthermore, the majority of patients become resistant to sorafenib. Recently, computational methods for drug repurposing have shown great promise to accelerate the discovery of new uses for existing drugs. In order to identify novel drugs for use against sorafenib resistant (SR)-HCC, we employed a transcriptomics-based drug repurposing method termed connectivity mapping. We conducted a comprehensive analysis of available in vitro and in vivo gene signatures of (SR)-HCC, and generated our own in vitro model using the Huh7 HCC cell line. We compared coverage of SR-HCC gene signatures across seven patient-derived HCC gene expression datasets, and observed that patients harboring the Huh7 SR-HCC gene signature had significantly reduced survival. Utilizing the Huh7 SR-HCC gene signature, we applied connectivity mapping to drug-induced gene expression profiles (n= 3,740 drugs) in the HepG2 HCC cell line from the LINCS database in order to find drugs that could oppose sorafenib resistance. We validated the use of two non-receptor tyrosine kinase inhibitors, dasatinib and fostamatinib, to reduce viability of sorafenib-resistant HCC cells and confirmed up-regulated activity of Src family kinases, the targets of dasatinib, in our SR-HCC models. We prospectively validated predicted gene expression changes in fostamatinib treated Huh7-SR via RNA-seq analysis.
2019-09-01 | GSE113005 | GEO
Project description:In our experiments with a xenograft model, mouse-IFN (mIFN) treatment was suggested to exaggerate the antitumor effects of sorafenib on hepatocellular carcinoma in vivo. We explored how mIFN enhances the in vivo antitumor effects of sorafenib.
2017-11-01 | GSE102863 | GEO
Project description:Background & Aims: Existing drug therapies for hepatocellular carcinoma (HCC), including sorafenib, extend patient survival by only three months. We sought to identify novel druggable targets for use in combination with sorafenib to increase its efficacy. Methods: We implemented an in vivo genetic screening paradigm utilizing a library of 43 genes-of-interest expressed in the context of repopulation of the injured livers of Fumarylacetoacetate Hydrolase-deficient (Fah-/-) mice, which led to highly penetrant HCC. We treated mice with vehicle or sorafenib, then determined the genetic drivers of each tumor from the library. Liver X Receptor alpha (LXRalpha) emerged as a potential target. To examine LXRalpha agonism in combination with sorafenib treatment, we added varying concentrations of sorafenib and LXRalpha agonist drugs to HCC cell lines. To elucidate the mechanism of tumor death, we performed transcriptomic analysis. Results: Fah-/- mice injected with the screening library developed HCC tumor clones containing Myc cDNA plus various other cDNAs. Treatment with sorafenib resulted in sorafenib-resistant HCCs that were significantly depleted in Nr1h3 cDNA, encoding LXRalpha, suggesting that LXRalpha activation is incompatible with tumor growth in the presence of sorafenib treatment in vivo. Combination treatment using sorafenib and LXR agonist drugs in multiple HCC cell lines led to enhanced cell death as compared to monotherapy, due to reduced expression of cell cycle regulators and increased expression of genes associated with apoptosis. Combination therapy also enhanced cell death in a sorafenib-resistant primary human HCC cell line. Conclusions: We have completed a novel drug resistance screen in vivo, and identified that LXR agonism potentiates the efficacy of sorafenib in treating HCC.
2020-05-29 | GSE151412 | GEO
Project description:Sorafenib, the first targeted therapy for hepatocellular carcinoma (HCC), has been utilized in clinics over a decade. However, its effectiveness is severely hindered by the acquired drug resistance, the mechanisms of which remain largely elusive. In this study, we identify that carbonic anhydrase 2 (CA2) is a key regulator of sorafenib resistance. Mechanistically, sorafenib treatment decreases intracellular pH (pHi) by suppressing monocarboxylate transporter 4 (MCT4) expression, while high levels of CA2 counteract MCT4-mediated pHi dysregulation upon sorafenib treatment, maintaining pHi homeostasis to facilitate cell survival and sorafenib resistance. Targeting CA2 re-sensitizes resistant HCC cells to sorafenib both in vitro and in vivo. Importantly, analysis of clinical samples demonstrates a strong correlation between CA2 expression levels and the therapeutic efficacy of sorafenib in HCC patients. Our findings highlight the significance of CA2 in facilitating sorafenib resistance and propose targeting CA2 as a potential strategy for overcoming sorafenib resistance in HCC patients.
2024-10-24 | PXD056884 | Pride
Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.
2016-06-16 | E-GEOD-73571 | biostudies-arrayexpress
Project description:Sorafenib, a multiple-kinase inhibitor, has been widely used as a first-line anticancer drug for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance to sorafenib is frequently observed in clinical applications. Potential non-kinase targets of sorafenib have not been well documented and may provide insights into reversing drug resistance. Herein, we report that sorafenib exerted its anticancer effects by activating metallothionein 1G (MT1G) expression. MT1G served as a novel marker in HCC and correlated well with patient survival. MT1G overexpression suppressed the cellular proliferation, migration, invasion, and tumor formation of HCC, and sensitized cells to sorafenib treatment. However, the disruption of MT1G attenuated sorafenib’s anticancer effects. Mechanistically, sorafenib upregulated MT1G expression via hypomethylation of its promoter region by binding and inhibiting DNA methyltransferase 1 (DNMT1) and increasing its promoter accessibility in HCC cells. The activation of MT1G also inhibited CA9 transcription through the degradation of HIF1a as mediated by KLF4. Our collective data revealed that sorafenib exerted its anticancer effects through epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis in HCC, and that the activation of MT1G might constitute a strategy for reversing sorafenib resistance.
2022-04-30 | GSE192771 | GEO
Project description:Hepatocellular carcinoma (HCC) is often diagnosed in patients with advanced disease who are ineligible for curative surgical therapies. Sorafenib, a multi-kinase inhibitor, is currently the only approved drug used in treating such patients. However, patients rapidly become unresponsive due to inherent and acquired drug resistance. To better understand the molecular mechanisms underlying sorafenib resistance in HCC at a global level in an unbiased manner, we conducted gene expression analysis using in vitro models of HCC sorafenib resistance using the Huh7 cell line, including a resistant pool of cells and a specific clone derived from the resistant pool.
2019-09-01 | GSE94550 | GEO
Project description:Aims: Metformin is a widely used, primary drug of choice to treat individuals with type 2 diabetes (T2D). Clinically, inter-individual variability of drug response is of significant concern. The targets and precise mechanisms of action for metformin is still under interrogation. In the present study, a whole transcriptome analysis was performed with an intent to identify predictive biomarkers of metformin response in T2D individuals. Methods: Twenty drug naïve individuals with T2D and ten healthy controls were enrolled. T2D individuals were administrated with metformin monotherapy and were defined as responders and non-responders based on the changes in their glycated haemoglobin (HbA1c) over a period of three months. Poly(A) RNA Seq was performed using Ion Torrent Proton platform and differentially expressed genes were identified from the transcriptome profiles. The gene prioritization, enrichment analysis, drug-gene interactions, disease gene association analysis were performed using various tools and databases. A correlation analysis was also performed between gene expression and change in HbA1c levels after 3 months of metformin therapy. Results: The expression analysis highlighted differentially expressed genes in metformin responders, non-responders and healthy individuals. The gene prioritization and enrichment analysis highlighted potential targets for predicting metformin response (n=35) as well as T2D disease (n=14). The drug-gene interactions did not show any direct association with diabetes drugs. However, the expression of GDF15, TWISTNB and RPL36A genes showed maximum correlation with change in HbA1c levels after 3 months of metformin therapy. The disease gene association analysis highlighted rs113805659 in MAGI2 gene to be linked with T2D in African Americans. Conclusion: The results of the present study provide evidence for the perturbed transcriptome and pathways associated with metformin drug response in T2D individuals.
2022-06-30 | GSE153315 | GEO
Project description:Objective: identify novel and relevant aspects of Sorafenib action on liver cancer cells. We found that in rat hepatocholangiocarcinoma (LCSC-2) cells, exposure to the MEK/multikinase inhibitor sorafenib did not inhibit ERK phosphorylation nor induced appreciable cell death in the low micromolar range; instead, the drug elicited a raise of intracellular reactive oxygen species (ROS) accompanied by a severe decrease of oxygen consumption and intracellular ATP levels, all changes consistent with mitochondrial damage. Moreover, Sorafenib induced depolarization of isolated rat liver mitochondria, indicating a possible direct effect on the organelle. Microarray analysis of gene expression in sorafenib-trated cells revealed a metabolic reprogramming toward aerobic glycolysis, that likely accounts for resitance to drug toxicity in this cell line. Importantly, cytotoxicity was strongly potentiated by glucose withdrawal from the culture medium or by the glycolytic inhibitor 2-deoxy-glucose, a finding also confirmed in the highly malignant melanoma cell line B16F10. Mechanistic studies revealed that ROS are pivotal to cell killing by the Sorafenib + 2DG combination, and that a low content of intracellular oxidants is associated with resistance to the drug; instead, Thr172phosphorylation/activation of the AMP-activated protein kinase (AMPK), induced by Sorafenib, may exert protective effects, since cytotoxicity was enhanced by an AMPK specific inhibitor and prevented by the AMPK activator Metformin. Overall, this study identifies novel and relevant aspects of Sorafenib action on liver cancer cells, including mitochondrial damage, induction of ROS and a metabolic cell reprogramming towards “glucose addiction”, potentially exploitable in therapy.
2015-02-04 | GSE43053 | GEO