The inhibitory effects of camptothecin, a topoisomerase I inhibitor, on collagen synthesis in fibroblasts from patients with systemic sclerosis

Czuwara-Ladykowska, Joanna; Makiela, Barbara; Smith, Edwin A.; Trojanowska, Maria; Rudnicka, Lidia

doi:10.1186/ar321

Cited by 12 publications

(7 citation statements)

References 34 publications

(42 reference statements)

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“…46 Irinotecan is an analogue of camptothecin (CPT), 47 a topoisomerase I inhibitor capable of reducing collagen production in SSc fibroblasts. 48 It could be argued that RNA-seq analysis of specific leucocyte subsets could theoretically have been more informative compared with WB analysis. 49 50 Nonetheless, available methods for subsetspecific expression profiling are ill-suited for large studies and the choice of the cell type to analyse is not obvious.…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients

et al. 2020

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ObjectivesThe analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations.MethodsSamples from 162 patients and 252 controls were collected in RNA stabilisers. Cases and controls were divided into a discovery (n=79+163; Southern Europe) and validation cohort (n=83+89; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. In parallel, immunophenotyping of 28 circulating cell populations was performed. We tested the presence of differentially expressed genes/pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated.ResultsOverall, 15 224 genes and 1277 functional pathways were available; of these, 99 and 225 were significant in both sets. Among replicated pathways, we found a deregulation in type-I interferon, Toll-like receptor cascade, tumour suppressor p53 protein function, platelet degranulation and activation. RNA transcripts or FAIME scores were jointly correlated with cell subtypes with strong geographical differences; neutrophils were the major determinant of gene expression in SSc-WB samples.ConclusionsWe discovered a set of differentially expressed genes/pathways validated in two independent sets of patients with SSc, highlighting a number of deregulated processes that have relevance for the pathogenesis of autoimmunity and SSc.

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Section: Discussionmentioning

confidence: 99%

“…46 Irinotecan is an analogue of camptothecin (CPT), 47 a topoisomerase I inhibitor capable of reducing collagen production in SSc fibroblasts. 48 …”

Section: Discussionmentioning

confidence: 99%

Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients

et al. 2020

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“…Over time, fibroblasts will migrate out of the tissue and populate the culture dish. The digestion/enzymatic method can also be utilized to obtain fibroblasts from skin (44) or lung (45). This method for the release of fibroblasts requires the use of enzymes, such as collagenase and deoxyribonuclease.…”

Section: Culture Of Fibroblasts and Representative Model Systemsmentioning

confidence: 99%

The Mighty Fibroblast and Its Utility in Scleroderma Research

Garrett

Frost

Feghali‐Bostwick

2017

Journal of Scleroderma and Related Disorders

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Fibroblasts are the effector cells of fibrosis characteristic of systemic sclerosis (SSc, scleroderma) and other fibrosing conditions. The excess production of extracellular matrix (ECM) proteins is the hallmark of fibrosis in different organs, such as skin and lung. Experiments designed to assess the pro-fibrotic capacity of factors, their signaling pathways, and potential inhibitors of their effects that are conducted in fibroblasts have paved the way for planning clinical trials in SSc. As such, fibroblasts have proven to be valuable tools in the search for effective anti-fibrotic therapies for fibrosis. Herein we highlight the characteristics of fibroblasts, their role in the etiology of fibrosis, utility in experimental assays, and contribution to drug development and clinical trials in SSc.

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“…Some recent findings have stressed that CPT influences DNA replication and transcription separately and the disturbances of the last process cause death of not proliferating cells [19,35]. Translation follows transcription so we could suspect inhibition of proteins production after CPT action on cells and there are such observations on fibroblasts and neurons [36,37] but not on melanoma or cells from other tumors.…”

Section: Discussionmentioning

confidence: 98%

Camptothecin-induced death of amelanotic and melanotic melanoma cells in different phases of cell cycle

Cichorek¹

2011

neo

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Camptothecin and its analogues are used as S-phase specific antitumor drugs because of topoisomerase I inhibition providing cells to death by apoptosis. Our previous works documented that amelanotic hamster's melanoma is very sensitive to camptothecin. Because of the challenges in treating melanoma and S-phase specificity of camptothecin, we performed a study to search what melanoma cell cycle phases are susceptible to this substance.Melanotic (Ma) and amelanotic (Ab) lines of Bomirski hamster's melanoma were used. Camptothecin cytotoxicity was determined by TUNEL method and cell cycle analysis was done by DNA staining with propidium iodide.Camptothecin after short time killed amelanotic melanoma cells from S/G2/M phases but with extended time dying cells came from G0/G1. Melanotic melanoma had fewer cells in S/G2/M phases and 3-fold more of these cells spontaneously died in comparison to more aggressive amelanotic line. High susceptibility of amelanotic melanoma cells to camptothecin show that not only cells with proliferative activity were sensitive to this alkaloid but with extended time it killed cells from all cycle phases. High number of cells in S/G2/M phases and low rate of spontaneous death among amelanotic melanoma cells suggest that the expansive growth of this melanoma line depends mainly on the decreased ability to undergo spontaneous apoptosis. If the sensitivity of amelanotic melanoma is not only hamster's but also human melanoma feature, we can suspect that by choosing melanoma form for treatment with camptothecin we could improve effectiveness of this drug against melanoma.

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The inhibitory effects of camptothecin, a topoisomerase I inhibitor, on collagen synthesis in fibroblasts from patients with systemic sclerosis

Cited by 12 publications

References 34 publications

Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients

Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients

The Mighty Fibroblast and Its Utility in Scleroderma Research

Camptothecin-induced death of amelanotic and melanotic melanoma cells in different phases of cell cycle

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