Drivers of topoisomerase II poisoning mimic and complement cytotoxicity in AML cells
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PROVIDER: PRJNA523616 | ENA |
REPOSITORIES: ENA
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Project description:Recently approved cancer drugs remain out-of-reach to most patients due to prohibitive costs and only few produce clinically meaningful benefits. An untapped alternative is to enhance the efficacy and safety of existing cancer treatments. We hypothesized that the response to topoisomerase II poisons, the most successful group of cancer drugs, can be improved by considering treatment-associated transcript levels, taken as surrogates for protein expression. To this end, we analyzed transcriptomes from Acute Myeloid Leukemia (AML) cell lines treated with the topoisomerase II poison etoposide. Using complementary criteria of co-regulation within networks and of essentiality for cell survival, we identified and functionally confirmed 11 druggable drivers of etoposide cytotoxicity. Drivers with pre-treatment expression predicting etoposide response (e.g. PARP9) generally synergized with the drug. Drivers repressed by etoposide (e.g. PLK1) displayed standalone cytotoxicity. Drivers, whose modulation evoked etoposide-like gene expression changes (e.g. mTOR), were cytotoxic both alone and in combination with etoposide. In summary, both pre-treatment gene expression and treatment-driven changes contribute to the cell killing effect of etoposide. Inhibitors of protein products of the involved genes can be used to enhance the efficacy of etoposide. This strategy can be used to identify combination partners or even replacements for other classical anticancer drugs, especially those interfering with DNA integrity and transcription.
2019-09-18 | GSE126895 | GEO
Project description: Not available
| S-EPMC6731103 | biostudies-literature
Project description:Complement activation induces excessive T cell cytotoxicity in severe COVID-19
| PRJNA732416 | ENA
Project description:Pharmacogenomic identification of targets for adjuvant therapy with the topoisomerase poison camptothecin. The response of tumor cells to the unusual form of DNA damage caused by topoisomerase poisons such as camptothecin (CPT) is poorly understood, and knowledge regarding which drugs can be effectively combined with CPT is lacking. To better understand the response of tumor cells to CPT and to identify potential targets for adjuvant therapy, we examined global changes in mRNA abundance in HeLa cells after CPT treatment using Affymetrix U133A GeneChips, which include all annotated human genes (22,283 probe sets). Statistical analysis of the data using a Bayesian/Cyber t test and a modified Benjamini and Hochberg correction for multiple hypotheses testing identified 188 probe sets that are induced and 495 that are repressed 8 h after CPT treatment at a False Discovery Rate of <0.05 and a minimum 3-fold change. This pharmacogenomic approach led us to identify two pathways that are CPT induced: (a) the epidermal growth factor receptor; and (b) nuclear factor-kappaB-regulated antiapoptotic factors. Experiments using HeLa cells in our lab and prior animal model studies performed elsewhere confirm that inhibitors of these respective pathways super-additively enhance CPT's cytotoxicity, suggesting their potential as targets for adjuvant therapy with CPT. Cancer Res. 2004 Mar 15;64(6):2096-104
2007-07-29 | E-GEOD-1417 | biostudies-arrayexpress
Project description:The cancer target enyzme topoisomerase 1 transiently cleaves one strand of chromosomal DNA to relax accumulated strain that can prevent transcription, replication or chromatin assembly. The topoisomerase 1 poison camptothecin and its synthetic analogs are widely used chemotherapeutics that act by trapping the enzyme on DNA in a ‘covalent complex’, resulting in persistent DNA damage and cell death. The prevailing model, interfacial inhibition, contends that the covalent complex is trapped by drug binding alone. In contrast, here we show that camptothecins produce extensive oxidative stress and that topoisomerase 1 is reactive with electrophilic second messengers of oxidative damage. We show that blocking oxidative stress in cells inhibits covalent complex formation by camptothecin, while electrophiles such as 4-hydroxynonenal are able to induce covalent complex formation in cells on their own. Towards mechanism of action, we show that 4-hydroxynonenal electrophilically modifies a cysteine within the DNA-binding active site of human topoisomerase 1. Taken together, our results suggest a mechanism in which oxidative stress mediates the effects of many topoisomerase 1 poisons, and suggest that this critical DNA-regulating enzyme may have a dual role as a sensor of cellular redox stress, linking oxidative stress to DNA damage response in cancer cells.
2021-03-24 | PXD018549 | Pride
Project description:Cytotoxicity compounds derived from microbial culture broths
2021-11-28 | MSV000088462 | GNPS
Project description:As part of an anti-cancer natural product drug discovery program, we recently identified eusynstyelamide B (EB), which displayed cytotoxicity against MDA-MB-231 breast cancer cells. Here, we investigated the mechanism of action of EB in the prostate cancer cell line LNCaP after a treatment with 5 uM for 24 h. Transcriptome profiling followed by pathway analysis suggested that EB activated DNA damage pathways in LNCaP cells. Consistent with this, Chk2 phosphorylation was increased, p21Cip/Waf1 was up-regulated and Cdc2 expression was strongly reduced by EB. Importantly, EB caused DNA double-strand breaks, yet did not directly interact with DNA. Analysis of topoisomerase II-mediated decatenation discovered that EB is a novel topoisomerase II poison.
2015-10-21 | GSE74212 | GEO
Project description:We report binding of Topoisomerase IV on the E. coli genome. We report the cleavage sites of Topoisomerase IV on the E. coli genome
2016-04-21 | GSE75641 | GEO
Project description:Identification of human topoisomerase 1 interactome in HCT116 cells
2023-05-03 | MSV000091847 | MassIVE
Project description:Genomic Run-on analysis of topoisomerase mutants (top1-delta/top2ts or top2ts) has been conducted at reference temperature for wt strain and at non-permissive temperature for wt and mutant strains. Keywords: Genomic Run On
2010-02-16 | GSE16673 | GEO