Evaluation of a camptothetin analog, Topotecan, as an HIV "block and lock" agent
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ABSTRACT:
PROVIDER: PRJNA890303 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21897151_1.fastq.gz | Fastqsanger.gz | |||
| SRR21897151_2.fastq.gz | Fastqsanger.gz | |||
| SRR21897152_1.fastq.gz | Fastqsanger.gz | |||
| SRR21897152_2.fastq.gz | Fastqsanger.gz | |||
| SRR21897153_1.fastq.gz | Fastqsanger.gz |
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Project description:The goal of this study was to investigate transcriptome remodeling induced by treatment with a camptothetin analog, Topotecan (TPT), of a primary T cell model of HIV latency. The study aimed to determine whether TPT has a global inhibitory effect on gene expression in primary CD4+ T cells, and identify mechanisms of action of this drug as an HIV “block and lock” agent. Methods: CD4+ T cells were isolated from blood of HIV seronegative study participants (N=3) and utilized to generate an in vitro model of latent HIV infection (model developed in the Spina laboratory and previously described by Spina et al., 2013 and Soto et al., 2022). Following generation of the model, cells were treated with 10 uM Topotecan or its solvent dimethyl sulfoxide (DMSO) for 24 hours. Cells were lyzed with RLT buffer containing beta-mercaptoethanol from a RNeasy micro kit (Qiagen, Inc. cat # 74004). ERCC spikes (Thermo Fisher Scientific, Inc.) were added to cell lysates based on cell number in each sample (10 ul of 1:800 dilution per million cells). RNA was extracted and subjected to deep sequencing at the Institute for Genomics Medicine (IGM) Genomics Center at the University of California San Diego. Filtering low quality reads and removal of the 3’ adapter sequences were performed using the Trim Galore tool. Reads were mapped to the human genome (build hg38) using HISAT2, and to HIV and ERCC references using bowtie. Mapped human reads were counted against the human GENCODE annotation (v37) using HT-Seq. ERCC counts were used to determine whether TPT had global inhibitory effect on transcription in primary CD4+ T cells. Because no such effect was observed, differential gene expression analysis was performed using library EdgeR in Bioconductor R without correction of expression based on ERCC spikes. Genes with false discovery rate (FDR)-corrected p-value less than 0.05 and an absolute fold change in TPT-treated samples compared to DMSO controls greater than 2, were considered significantly modulated by TPT. Pathway and gene ontology (GO) term enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) v2022q3. Pathways and GO terms with FDR-corrected p-value less than 0.05 were considered significantly enriched for differentially expressed genes. Results: An average of 19.7 million reads per sample were acquired and mapped to the human genome (build hg38). After applying filtering criteria, 9,678 human genes were identified with the HISAT2 and HTSeq workflow. Differential expression analysis was performed between TPT- and DMSO-treated samples using EdgeR. A total of 1,749 differentially expressed genes (DEGs) were identified with FDR p-value <0.05 and an absolute fold change greater than 2; of which 522 were up- and 1227 downregulated by TPT. Pathway and GO term enrichment analysis revealed that TPT interferes with gene transcription and cell signaling pathways (e.g. T cell receptor signaling, positive regulation of JNK cascade, regulation of actin cytoskeleton and positive regulation of GTPase activity were affected by TPT treatment). Conclusion: The study demonstrated that TPT induces multiple effects on transcriptome in primary CD4+ T cells. Some of these changes may represent direct and indirect mechanisms of action of TPT as an HIV “block and lock” agent.
2023-01-20 | GSE215461 | GEO
Project description:Danger-associated molecular patterns (DAMPs) derived from damaged or dying cells not only elicit inflammation but also potentiate antitumor immune responses. Here, we show that treatment of breast cancer cells with the antitumor agent Topotecan, an inhibitor of topoisomerase I, induces DAMP secretion that triggers dendritic cell activation and cytokine production.
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Project description:To investigate mechanisms and differential gene expressions in topotecan-induced DNA damage and effects of ascorbic acid/hydrogen peroxide on these genes in topotecan cytotoxicity in tumor cells
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Project description:An alternative or follow-up adjunct to conventional maximum tolerated dose (MTD) chemotherapy now in advanced phase III clinical trial assessment is metronomic chemotherapy?the close regular administration of low doses of drug with no prolonged breaks. A number of preclinical studies have shown metronomic chemotherapy can cause long term survival of mice with advanced cancer, including metastatic disease, in the absence of overt toxicity, especially when combined with targeted antiangiogenic drugs. However, similar to MTD chemotherapy acquired resistance eventually develops, the basis of which is unknown. Using a preclinical model of advanced human ovarian (SKOV-3-13) cancer in SCID mice, we show that acquired resistance can develop after terminating prolonged (over 3 months) successful therapy utilizing daily oral metronomic topotecan plus pazopanib, an oral antiangiogenic tyrosine kinase inhibitor (TKI). Two resistant sublines were isolated from a single mouse, one from a solid tumor (called KH092-7SD, referred to as 7SD) and another from ascites tumor cells (called KH092-7AS, referred to as 7AS). Using these sublines we show acquired resistance to the combination treatment is due to tumor cell alterations that confer relative refractoriness to topotecan. The resistant phenotype is heritable, associated with reduced cellular uptake of topotecan and could not be reversed by switching to MTD topotecan or to another topoisomerase-1 inhibitor, CPT-11, given either in a metronomic or MTD manner nor switching to another antiangiogenic drug, e.g. the anti-VEGFR-2 antibody, DC101, or another TKI, sunitinib. Thus, in this case cross resistance seems to exist between MTD and metronomic topotecan, the basis of which is unknown. However, gene expression profiling revealed several potential genes that are stably upregulated in the resistant lines, that previously have been implicated in resistance to various chemotherapy drugs, and which, therefore, may contribute to the drug resistant phenotype. Two-condition experiment, ovarian cell line (SKOV-3-13) sensitive to daily oral metronomic topotecan plus pazopaniband treatemnt compared to two in- vivo selected resistant sublines from a solid tumor (called KH092-7SD) and another from ascites tumor cells (called KH092-7AS). Biological replicates: 4 independently grown and harvested cell line passages. Two technical replicate per condition (including dye swap).
2014-02-04 | E-GEOD-54621 | biostudies-arrayexpress
Project description:In order to address the treatment difficulties associated with chemotherapetic resistance in ovarian cancer, we combined our compounds with topotecan and admininstered the mixture to chemoresistant Igrov1/T8 ovarian cancer cells in vitro and Igrov1/T8 xenografts in CB-17 SCID mice.
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Project description:Submerged Analog Habitat Environment Raw sequence reads
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Project description:An alternative or follow-up adjunct to conventional maximum tolerated dose (MTD) chemotherapy now in advanced phase III clinical trial assessment is metronomic chemotherapy?the close regular administration of low doses of drug with no prolonged breaks. A number of preclinical studies have shown metronomic chemotherapy can cause long term survival of mice with advanced cancer, including metastatic disease, in the absence of overt toxicity, especially when combined with targeted antiangiogenic drugs. However, similar to MTD chemotherapy acquired resistance eventually develops, the basis of which is unknown. Using a preclinical model of advanced human ovarian (SKOV-3-13) cancer in SCID mice, we show that acquired resistance can develop after terminating prolonged (over 3 months) successful therapy utilizing daily oral metronomic topotecan plus pazopanib, an oral antiangiogenic tyrosine kinase inhibitor (TKI). Two resistant sublines were isolated from a single mouse, one from a solid tumor (called KH092-7SD, referred to as 7SD) and another from ascites tumor cells (called KH092-7AS, referred to as 7AS). Using these sublines we show acquired resistance to the combination treatment is due to tumor cell alterations that confer relative refractoriness to topotecan. The resistant phenotype is heritable, associated with reduced cellular uptake of topotecan and could not be reversed by switching to MTD topotecan or to another topoisomerase-1 inhibitor, CPT-11, given either in a metronomic or MTD manner nor switching to another antiangiogenic drug, e.g. the anti-VEGFR-2 antibody, DC101, or another TKI, sunitinib. Thus, in this case cross resistance seems to exist between MTD and metronomic topotecan, the basis of which is unknown. However, gene expression profiling revealed several potential genes that are stably upregulated in the resistant lines, that previously have been implicated in resistance to various chemotherapy drugs, and which, therefore, may contribute to the drug resistant phenotype.
2014-02-04 | GSE54621 | GEO
Project description:Combinations of anticancer agents may have synergistic anti-tumor effects, but enhanced hematological toxicity often limit their clinical use. We examined whether M-bM-^@M-^\microarray profilesM-bM-^@M-^] could be used to compare early molecular responses following a single dose of agents administered individually with that of the agents administered in a combination. Six patterns of co-expressed genes were detected at the 1-hour time point which indicate regulatory expression of genes dependent on the order of the administration. When topotecan is given first, several signal transduction transcription factors associated with cancer or inactivation of a tumor suppressor were co-regulating gene expression. These results suggest alterations in histone biology, chromatin remodeling, DNA repair, bone regeneration, and respiratory and oxidative phosphorylation are among the prominent pathways modulated in bone marrow from animals treated with an oxaliplatin/topotecan combination. mRNA responses were compared within bone marrow of Sprague-Dawley rats after a single 30-minute treatment with topotecan at 4.7 mg/kg or oxaliplatin at 15 mg/kg alone to that of sequentially administered combination therapy or vehicle control Please note that one of the 'Bone Marrow_Oxaliplatin _Vehicle 1' sample (1344-05H_4M 40) was considered an outlier and thus, was excluded from data analysis and GEO records.
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