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Artesunate shows potent anti-tumor activity in B-cell lymphoma by inducing ER-stress response

ABSTRACT: Artesunate shows potent anti-tumor activity in B-cell lymphoma by inducing ER-stress response

ORGANISM(S): Homo sapiens

PROVIDER: GSE94553 | GEO | 2017/02/07

SECONDARY ACCESSION(S): PRJNA371488

REPOSITORIES: GEO

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Artesunate shows potent anti-tumor activity in B-cell lymphoma.

Project description:BACKGROUND:Although chemo-immunotherapy has led to an improved overall survival for most B-cell lymphoma types, relapsed and refractory disease remains a challenge. The malaria drug artesunate has previously been identified as a growth suppressor in some cancer types and was tested as a new treatment option in B-cell lymphoma. METHODS:We included artesunate in a cancer sensitivity drug screen in B lymphoma cell lines. The preclinical properties of artesunate was tested as single agent in vitro in 18 B-cell lymphoma cell lines representing different histologies and in vivo in an aggressive B-cell lymphoma xenograft model, using NSG mice. Artesunate-treated B lymphoma cell lines were analyzed by functional assays, gene expression profiling, and protein expression to identify the mechanism of action. RESULTS:Drug screening identified artesunate as a highly potent anti-lymphoma drug. Artesunate induced potent growth suppression in most B lymphoma cells with an IC50 comparable to concentrations measured in serum from artesunate-treated malaria patients, while leaving normal B-cells unaffected. Artesunate markedly inhibited highly aggressive tumor growth in a xenograft model. Gene expression analysis identified endoplasmic reticulum (ER) stress and the unfolded protein response as the most affected pathways and artesunate-induced expression of the ER stress markers ATF-4 and DDIT3 was specifically upregulated in malignant B-cells, but not in normal B-cells. In addition, artesunate significantly suppressed the overall cell metabolism, affecting both respiration and glycolysis. CONCLUSIONS:Artesunate demonstrated potent apoptosis-inducing effects across a broad range of B-cell lymphoma cell lines in vitro, and a prominent anti-lymphoma activity in vivo, suggesting it to be a relevant drug for treatment of B-cell lymphoma.

| S-EPMC5819282 | biostudies-literature

Artesunate inhibits the cell viability of diffuse large B cell lymphoma cells by increasing the susceptibility to ferroptosis (RNA-seq).

Project description:Comparing the effects of artesunate versus DMSO in three DLBCL cell lines, we found a decrease in cell viability to 80%-60%. Over increasing artesunate dosage,we found increasing ROS generation and lipid peroxidation. In combination with the Ferrostatin-1 rescue experiment, we conclude that cell death induced by artesunate is ferroptotic. We compared the transcriptome of the U2932 cell line with and without 100µm artesunate in triplicate. A ferroptosis gene signature is shown to be enriched among the upregulated genes of this comparison. GPX4 protein expression was shown to be downregulated after artesunate in U2932 cells, but not in the rescue experiment with Ferrostatin-1. MT1G gene expression was identified as required for artesunate-mediated ferroptosis via targeted suppression by shRNAs. We present significantly decreased cell viability when combining artesunate with doxorubicin, suggesting a potential translation into clinic for treatment of ABC and GCB DLBCL.

2024-03-06 | GSE260741 | GEO

Differential Gene expression anslysis between artesunate sensitive and resistat Leishmania donovani

Project description:Gene expression analysis was carried out between experimental artesunate resistant Leishmania donovani (adapted to 50 µM artesunate drug pressure) and it's corresponding wild type artesunate sensitive parasite.

2019-08-30 | GSE118460 | GEO

Exploring the molecular mechanism of artesunate intervening in glioma based on DNA methylation sequencing technology

Project description:Whole gene methylation profiles of U87 and U251 glioma cells before and after artesunate treatment, Infinium MethylationEPIC BeadChip, samples including 3 U87 cell normal group, 3 U251 cell normal group, 3 artesunate treated U87 cell group, U251 cell group was treated with 3 artesunate.

2022-10-18 | GSE215784 | GEO

Transcription profiling of Plasmodium falciparum synchronized blood stages exposed to lethal doses of artesunate

Project description:Each experiment consisted in an artesunate-free culture (control) and an artesunate treated culture. For each time point explored, cDNA from parasites with and without the drug were labeled with different cyanines, mixed and hybridized. To analyse dynamic transcriptome alterations, two pilot experiments were performed in which RNA was harvested at 90 and 180 minutes of incubation with the drug. <br><br> Since artesunate is active on ring stages as well as on older trophozoite stages, we decided to explore different time points along the erythrocytic cycle and search for genes affected at each time point. Therefore, five drug treatment experiments, staggered between 20 hours and 30 hours of parasite development, were performed for the comparison of drug versus no drug at 90 minutes and 3 hours. <br><br> Different expression levels in artesunate-exposed vs. control unexposed cultures could reflect the added effects of the actual response to artesunate together with a possible difference in growth rate/developmental stage. To identify the developmentally regulated genes in the artesunate-free control culture, the 3 hours RNA was hybridized against the time 0 RNA (3 control experiments).

2008-06-01 | E-MEXP-1435 | biostudies-arrayexpress

Alkylating Agent-Induced ER Stress Overcomes Microenvironmental Resistance to Lymphoma Therapy

Project description:Compartment-specific resistance to cancer therapy remains poorly understood. We utilized orthotopic xenografts of human double-hit lymphoma (DHL) to interrogate responses across involved sites. We identified resistance to multiple chemotherapies and the anti-CD52 antibody Alemtuzumab within the bone marrow (BM) that depended on extensive lymphoma involvement and impaired antibody-dependent cellular phagocytosis. This resistance was overcome by high doses of alkylating agents, including cyclophosphamide (CTX), which exhibited >80-fold in vivo synergy with Alemtuzumab. CTX induced ER stress in BM DHL cells leading to ATF4- mediated paracrine secretion of VEGF-A and massive macrophage infiltration. Macrophages from DHL-engrafted, CTX-treated mice had increased phagocytic capacity for lymphoma cells that was reversed by VEGF-A blockade and required SYK phosphorylation. A subset of these macrophages, defined by surface CD36/FcgRIV and a distinct transcriptional state, were “super- phagocytic.” Together, our findings define a unique mechanism through which high-dose alkylating agents can overcome therapy-resistant niches by ER stress-induced activation of phagocytosis.

2020-03-01 | GSE128728 | GEO

N-Quinoline Benzenesulfonamide Derivatives Exert Potent Anti-Lymphoma effect by Targeting NF-κB

Project description:We perform expression analysis on lymphoma cell line OCI-Ly10 treated with a novel NF-kB translocation inhibitor CU-O75

2020-11-18 | GSE161677 | GEO

Artesunate overcomes the resistance of basal type of bladder cancer to RC48

Project description:ERBB2 expression mediates sensitivity of bladder cancer cells to RC48. JAK/STAT3 pathways compensatory activation after exposing RC48. A combination of STAT3 inhibitor-artesunate and RC48 could significantly inhibit basal bladder cancer growth. These findings provided a theoretical foundation for subsequent individualized therapy for MIBC based on the molecular types.

2024-06-01 | GSE237789 | GEO

RNA-seq analysis of the mouse brain reveals inflammatory genes associated with early artesunate treatment of experimental cerebral malaria

Project description:Purpose:This study aimed to investigate the transcriptome-wide response of experimental cerebral malaria (ECM) and artesunate treated mice brain on 6 days post-infection. Methods: C57BL/6 mice were infected with Plasmodium berghei ANKA to construct a murine ECM in MB and AB group. AB group treated with artesunate (30mg/kg), while CB group treated with PBS for 4 days. Mice brain was tested by RNA-seq. Results: Gene ontology and KEGG pathway analyses of differentially expressed genes (DEGs) were performed. quantitative reverse transcription polymerase chain reaction (qPCR) verify DEGs such as Il6, Il1b, Il10, Tnf, Ifng, Il21, Icam1, which were up-regulated in MB vs. CB, while down-regulated in AB vs. MB. Conclusions:Our study revealed a transcriptome-wide profile in ECM and artesunate treated mice brain, and help to explore the underlying mechanism, as well as the further development of therapeutic strategies for clinical cerebral malaria.

2022-12-02 | GSE162535 | GEO