Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A comparative analysis of the mutagenicity of platinum-containing chemotherapeutic agents reveals direct and indirect mutagenic mechanisms.

ABSTRACT: Platinum-based drugs are a mainstay of cancer chemotherapy. However, their mutagenic effect can increase tumour heterogeneity, contribute to the evolution of treatment resistance and also induce secondary malignancies. We coupled whole genome sequencing with phenotypic investigations on two cell line models to compare the magnitude and examine the mechanism of mutagenicity of cisplatin, carboplatin and oxaliplatin. Cisplatin induced significantly more base substitution mutations than carboplatin or oxaliplatin when used at equitoxic concentrations on human TK6 or chicken DT40 cells, and also induced the highest number of short insertions and deletions. The analysis of base substitution spectra revealed that all three tested platinum drugs elicit both a direct mutagenic effect at purine dinucleotides, and an indirect effect of accelerating endogenous mutagenic processes, whereas the direct mutagenic effect appeared to correlate with the level of DNA damage caused as assessed through histone H2AX phosphorylation and single-cell agarose gel electrophoresis, the indirect mutagenic effects were equal. The different mutagenicity and DNA-damaging effect of equitoxic platinum drug treatments suggest that DNA damage independent mechanisms significantly contribute to their cytotoxicity. Thus, the comparatively high mutagenicity of cisplatin should be taken into account in the design of chemotherapeutic regimens.

SUBMITTER: Szikriszt B

PROVIDER: S-EPMC8081379 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress.

Project description:Cisplatin and its platinum analogs, carboplatin and oxaliplatin, are some of the most widely used cancer chemotherapeutics. Although cisplatin and carboplatin are used primarily in germ cell, breast and lung malignancies, oxaliplatin is instead used almost exclusively to treat colorectal and other gastrointestinal cancers. Here we utilize a unique, multi-platform genetic approach to study the mechanism of action of these clinically established platinum anti-cancer agents, as well as more recently developed cisplatin analogs. We show that oxaliplatin, unlike cisplatin and carboplatin, does not kill cells through the DNA-damage response. Rather, oxaliplatin kills cells by inducing ribosome biogenesis stress. This difference in drug mechanism explains the distinct clinical implementation of oxaliplatin relative to cisplatin, and it might enable mechanistically informed selection of distinct platinum drugs for distinct malignancies. These data highlight the functional diversity of core components of front-line cancer therapy and the potential benefits of applying a mechanism-based rationale to the use of our current arsenal of anti-cancer drugs.

| S-EPMC5520548 | biostudies-literature

Sec61? controls sensitivity to platinum-containing chemotherapeutic agents through modulation of the copper-transporting ATPase ATP7A.

Project description:The Sec61 protein translocon is a multimeric complex that transports proteins across lipid bilayers. We discovered that the Sec61? subunit modulates cellular sensitivity to chemotherapeutic agents, particularly the platinum drugs. To investigate the mechanism, expression of Sec61? was constitutively knocked down in 2008 ovarian cancer cells. Sec61? knockdown (KD) resulted in 8-, 16.8-, and 9-fold resistance to cisplatin (cDDP), carboplatin, and oxaliplatin, respectively. Sec61? KD reduced the cellular accumulation of cDDP to 67% of that in parental cells. Baseline copper levels, copper uptake, and copper cytotoxicity were also reduced. Because copper transporters and chaperones regulate platinum drug accumulation and efflux, their expression in 2008 Sec61?-KD cells was analyzed; ATP7A was found to be 2- to 3-fold overexpressed, whereas there was no change in ATP7B, ATOX1, CTR1, or CTR2 levels. Cells lacking ATP7A did not exhibit increased cDDP resistance upon knockdown of Sec61?. Sec61?-KD cells also exhibited altered ATP7A cellular distribution. We conclude that Sec61? modulates the cytotoxicity of many chemotherapeutic agents, with the largest effect being on the platinum drugs. This modulation occurs through effects of Sec61? on the expression and distribution of ATP7A, which was shown previously to control platinum drug sequestration and cytotoxicity.

| S-EPMC3422700 | biostudies-literature

DNA polymerase ? is a major determinant of resistance to platinum-based chemotherapeutic agents.

Project description:Oxaliplatin, satraplatin, and picoplatin are cisplatin analogs that interact with DNA forming intrastrand and interstrand DNA cross-links (ICLs). Replicative bypass of cisplatin DNA adducts requires the cooperative actions of at least three translesion DNA synthesis (TLS) polymerases: Pol?, REV1, and Pol?. Because oxaliplatin, satraplatin, and picoplatin contain bulkier chemical groups attached to the platinum core compared with cisplatin, we hypothesized that these chemical additions may impede replicative bypass by TLS polymerases and reduce tolerance to platinum-containing adducts. We examined multiple responses of cancer cells to oxaliplatin, satraplatin, or picoplatin treatment under conditions where expression of a TLS polymerase was limited. Our studies revealed that, although Pol? contributes to the tolerance of cisplatin adducts, it plays a lesser role in promoting replication through oxaliplatin, satraplatin, and picoplatin adducts. REV1 and Pol? were necessary for tolerance to all four platinum analogs and prevention of hyperactivation of the DNA damage response after treatment. In addition, REV1 and Pol? were important for the resolution of DNA double-stranded breaks created during replication-associated repair of platinum-containing ICLs. Consistent with ICLs being the predominant cytotoxic lesion, depletion of REV1 or Pol? rendered two different model cell systems extremely sensitive to all four drugs, whereas Pol? depletion had little effect. Together, our data suggest that REV1 and Pol? are critical for promoting resistance to all four clinically relevant platinum-based drugs by promoting both translesion DNA synthesis and DNA repair.

| S-EPMC3362893 | biostudies-other

Mechanisms of Cardiotoxicity of Cancer Chemotherapeutic Agents: Cardiomyopathy and Beyond.

Project description:Tremendous strides have been made in the treatment of various oncological diseases such that patients are surviving longer and are having better quality of life. However, the success has been tainted by the iatrogenic cardiac toxicities. This is especially concerning in the younger population who are facing cardiac disease such as heart failure in their 30s and 40s as the consequence of the anthracycline's side effects (used for childhood leukemia and lymphoma). This resulted in the awareness of cardiotoxic effects of anticancer drugs and emergence of a new discipline: oncocardiology. Since then, numerous anticancer drugs have been correlated to cardiomyopathy. Additionally, other cardiovascular effects have been identified, which includes but is not limited to myocardial infarction, thrombosis, hypertension, arrhythmias, and pulmonary hypertension. In this review we examine some of the anticancer agents that mitigate cardiotoxicity and present current knowledge of molecular mechanism(s). The aim of the review is to ignite awareness of emerging cardiotoxic effects as new generations of anticancer agents are being tested in clinical trials and introduced as part of the therapeutic armamentarium to our oncological patients.

| S-EPMC4921299 | biostudies-literature

COVID-19: Direct and Indirect Mechanisms of Statins.

Project description:The virus responsible for the current COVID-19 pandemic is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): a new virus with high infectivity and moderate mortality. The major clinical manifestation of COVID-19 is interstitial pneumonia, which may progress to acute respiratory distress syndrome (ARDS). However, the disease causes a potent systemic hyperin-flammatory response, i.e., a cytokine storm or macrophage activation syndrome (MAS), which is associated with thrombotic complications. The complexity of the disease requires appropriate intensive treatment. One of promising treatment is statin administration, these being 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that exert pleiotropic anti-inflammatory effects. Recent studies indicate that statin therapy is associated with decreased mortality in COVID-19, which may be caused by direct and indirect mechanisms. According to literature data, statins can limit SARS-CoV-2 cell entry and replication by inhibiting the main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). The cytokine storm can be ameliorated by lowering serum IL-6 levels; this can be achieved by inhibiting Toll-like receptor 4 (TLR4) and modulating macrophage activity. Statins can also reduce the complications of COVID-19, such as thrombosis and pulmonary fibrosis, by reducing serum PAI-1 levels, attenuating TGF-β and VEGF in lung tissue, and improving endothelial function. Despite these benefits, statin therapy may have side effects that should be considered, such as elevated creatinine kinase (CK), liver enzyme and serum glucose levels, which are already elevated in severe COVID-19 infection. The present study analyzes the latest findings regarding the benefits and limitations of statin therapy in patients with COVID-19.

| S-EPMC8073792 | biostudies-literature

EWSR1 influences alternative splicing through direct and indirect mechanisms

Project description:FET family RNA binding proteins are implicated in cancer and neurological disorders and yet their biological function is incompletely understood. We used cross-linking and immunoprecipitation followed by high-throughput sequencing (HITS-CLIP) as well as gene expression and alternative splicing analysis by RNAseq to characterize the molecular function of the FET family RNA binding protein EWSR1. In HeLA cells, EWSR1 binding is enriched at 3’UTRs and at both 5’ exon/intron and 3’ intron/exon boundaries. RNAs bound by EWSR1 are functionally enriched for RNA binding and RNA processing genes, suggesting a key role for EWSR1 in RNA regulation. While EWSR1 knock-down altered expression of hundreds of genes, only a subset of the transcripts for these genes were directly bound by EWSR1. By overlapping the HITS-CLIP data with the RNAseq splicing analysis we identified genes where EWSR1 binding is more likely to directly affect splicing. EWSR1 regulated splicing events were varied and included exon inclusion, alternative 3 exon usage and intron retention. These results indicate that EWSR1 has pleiotropic effects on splicing and that these effects are caused both by direct regulation of splicing and through effects on a large number of RNAs that themselves code for splicing effectors. Further understanding of this complex splicing regulation network may be important to disentangle the role of EWSR1 in multiple human diseases.

2018-05-01 | GSE98836 | GEO

The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents.

Project description:Platinum-based anticancer drugs, including cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin, are heavily applied in chemotherapy regimens. However, the intrinsic or acquired resistance severely limit the clinical application of platinum-based treatment. The underlying mechanisms are incredibly complicated. Multiple transporters participate in the active transport of platinum-based antitumor agents, and the altered expression level, localization, or activity may severely decrease the cellular platinum accumulation. Detoxification components, which are commonly increasing in resistant tumor cells, can efficiently bind to platinum agents and prevent the formation of platinum-DNA adducts, but the adducts production is the determinant step for the cytotoxicity of platinum-based antitumor agents. Even if adequate adducts have formed, tumor cells still manage to survive through increased DNA repair processes or elevated apoptosis threshold. In addition, autophagy has a profound influence on platinum resistance. This review summarizes the critical participators of platinum resistance mechanisms mentioned above and highlights the most potential therapeutic targets or predicted markers. With a deeper understanding of the underlying resistance mechanisms, new solutions would be produced to extend the clinical application of platinum-based antitumor agents largely.

| S-EPMC7100275 | biostudies-literature

Chemoprotective activity of the isoflavones, genistein and daidzein on mutagenicity induced by direct and indirect mutagens in cultured HTC cells.

Project description:Isoflavones are phenolic compounds widely distributed in plants and found in a high percentage in soybeans. They have important biological properties and are regarded as potential chemopreventive agents. The aim of this study was to verify the preventive effect of two soy isoflavones (genistein and daidzein) by a micronucleus assay, analysis of GST activity, and real-time RT-PCR analysis of GSTa2 gene expression. Mutagens of direct (doxorubicin) and indirect (2-aminoanthracene) DNA damage were used. Hepatoma cells (HTC) were treated with genistein or daidzein for 26 h at noncytotoxic concentrations; 10 μM when alone, and 0.1, 1.0 and 10 μM when combined with genotoxic agents. The micronucleus test demonstrated that both isoflavones alone had no genotoxic effect. Genistein showed antimutagenic effects at 10 μM with both direct and indirect DNA damage agents. On phase II enzyme regulation, the current study indicated an increase in total cytoplasmic GST activity in response to genistein and daidzein at 10 μM supplementation. However, the mRNA levels of GSTa2 isozymes were not differentially modulated by genistein or daidzein. The results point to an in vitro antimutagenic activity of genistein against direct and indirect DNA damage-induced mutagenicity.

| S-EPMC3560877 | biostudies-literature

Polymeric micelles with ionic cores containing biodegradable cross-links for delivery of chemotherapeutic agents.

Project description:Novel functional polymeric nanocarriers with ionic cores containing biodegradable cross-links were developed for delivery of chemotherapeutic agents. Block ionomer complexes (BIC) of poly(ethylene oxide)-b-poly(methacylic acid) (PEO-b-PMA) and divalent metal cations (Ca(2+)) were utilized as templates. Disulfide bonds were introduced into the ionic cores by using cystamine as a biodegradable cross-linker. The resulting cross-linked micelles with disulfide bonds represented soft, hydrogel-like nanospheres and demonstrated a time-dependent degradation in the conditions mimicking the intracellular reducing environment. The ionic character of the cores allowed to achieve a very high level of doxorubicin (DOX) loading (50% w/w) into the cross-linked micelles. DOX-loaded degradable cross-linked micelles exhibited more potent cytotoxicity against human A2780 ovarian carcinoma cells as compared to micellar formulations without disulfide linkages. These novel biodegradable cross-linked micelles are expected to be attractive candidates for delivery of anticancer drugs.

| S-EPMC2854228 | biostudies-literature

FoxO3 modulates endothelial gene expression and function by direct and indirect mechanisms

Project description:FoxO transcription factors represent targets of the PI3K/PKB survival pathway controlling important biological processes such as stress responses, cell cycle progression, apoptosis, vascular remodelling and metabolism. Recent studies have demonstrated the existence of alternative mechanisms of FoxO-dependent gene expression beyond classical binding to a FoxO-responsive DNA binding element (FRE). Here we explored the relative contribution of those mechanisms by comparing the transcriptional responses to conditional activation of FoxO3 and a corresponding FRE-binding mutant in primary human endothelial cells. Microarray analysis revealed several functional gene clusters regulated in absence of an intact DNA-binding domain. Notably, both mutants triggered apoptosis albeit with different efficiencies. This was associated with regulation of overlapping and distinct proapototic gene clusters. Subsequent analysis demonstrated important roles for the Bcl2-like family members BIM and NOXA in this process. Remarkably, BIM was effectively induced by the FoxO3 FRE-binding mutant and BIM depletion could rescue its proapoptotic effect. Our study provides the first comprehensive analysis of alternatively regulated FoxO3 targets in primary cells and underscores the importance of such genes for endothelial function and integrity. HUVEC were infected in 4 independent experiments with either empty pBabe puro vector, pBP-FoxO3.A3.ER, or pBP FoxO3.A3.ER.H212R in three consecutive rounds and 72h post infection.

2010-01-31 | E-GEOD-16573 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data