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Cancer Treatment Reviews Jul 2024Small cell lung cancer (SCLC) is characterized by a dismal prognosis. Many efforts have been made so far for identifying novel biomarkers for a personalized treatment... (Review)
Review
Small cell lung cancer (SCLC) is characterized by a dismal prognosis. Many efforts have been made so far for identifying novel biomarkers for a personalized treatment for SCLC patients. Schlafen 11 (SLFN11) is a protein differently expressed in many cancers and recently emerged as a new potential biomarker. Lower expression of SLFN11 correlates with a worse prognosis in SCLC and other tumors. SLFN11 has a role in tumorigenesis, inducing replication arrest in the presence of DNA damage through the block of the replication fork. SLFN11 interacts also with chromatin accessibility, proteotoxic stress and mammalian target of rapamycin signalling pathway. The expression of SLFN11 is regulated by epigenetic mechanisms, including promoter methylation, histone deacetylation, and the histone methylation. The downregulation of SLFN11 correlates with a worse response to topoisomerase I and II inhibitors, alkylating agents, and poly ADP-ribose polymerase inhibitors in different cancer types. Some studies exploring strategies for overcoming drug resistance in tumors with low levels of SLFN11 showed promising results. One of these strategies includes the interaction with the Ataxia Telangiectasia and Rad3-related pathway, constitutively activated and leading to cell survival and tumor growth in the presence of low levels of SLFN11. Furthermore, the expression of SLFN11 is dynamic through time and different anticancer therapy and liquid biopsy seems to be an attractive tool for catching SLFN11 different expressions. Despite this, further investigations exploring SLFN11 as a predictive biomarker, its longitudinal changes, and new strategies to overcome drug resistances are needed.
Topics: Humans; Lung Neoplasms; Small Cell Lung Carcinoma; Biomarkers, Tumor; Nuclear Proteins; Antineoplastic Agents; RNA Splicing Factors; Prognosis
PubMed: 38797062
DOI: 10.1016/j.ctrv.2024.102768 -
Microorganisms May 2024Pradofloxacin is the newest of the veterinary fluoroquinolones to be approved for use in animals-initially companion animals and most recently food animals. It has a...
Comparative In Vitro Killing by Pradofloxacin in Comparison to Ceftiofur, Enrofloxacin, Florfenicol, Marbofloxacin, Tildipirosin, Tilmicosin and Tulathromycin against Bovine Respiratory Bacterial Pathogens.
Pradofloxacin is the newest of the veterinary fluoroquinolones to be approved for use in animals-initially companion animals and most recently food animals. It has a broad spectrum of in vitro activity, working actively against Gram-positive/negative, atypical and some anaerobic microorganisms. It simultaneously targets DNA gyrase (topoisomerase type II) and topoisomerase type IV, suggesting a lower propensity to select for antimicrobial resistance. The purpose of this study was to determine the rate and extent of bacterial killing by pradofloxacin against bovine strains of and , in comparison with several other agents (ceftiofur, enrofloxacin, florfenicol, marbofloxacin, tildipirosin, tilmicosin and tulathromycin) using four clinically relevant drug concentrations: minimum inhibitory and mutant prevention drug concentration, maximum serum and maximum tissue drug concentrations. At the maximum serum and tissue drug concentrations, pradofloxacin killed 99.99% of cells following 5 min of drug exposure (versus growth to 76% kill rate for the other agents) and 94.1-98.6% of following 60-120 min of drug exposure (versus growth to 98.6% kill rate for the other agents). Statistically significant differences in kill rates were seen between the various drugs tested depending on drug concentration and time of sampling after drug exposure.
PubMed: 38792823
DOI: 10.3390/microorganisms12050996 -
International Journal of Molecular... May 2024Triple-negative breast cancer (TNBC) remains the most lethal subtype of breast cancer, characterized by poor response rates to current chemotherapies and a lack of...
Triple-negative breast cancer (TNBC) remains the most lethal subtype of breast cancer, characterized by poor response rates to current chemotherapies and a lack of additional effective treatment options. While approximately 30% of patients respond well to anthracycline- and taxane-based standard-of-care chemotherapy regimens, the majority of patients experience limited improvements in clinical outcomes, highlighting the critical need for strategies to enhance the effectiveness of anthracycline/taxane-based chemotherapy in TNBC. In this study, we report on the potential of a DNA-PK inhibitor, peposertib, to improve the effectiveness of topoisomerase II (TOPO II) inhibitors, particularly anthracyclines, in TNBC. Our in vitro studies demonstrate the synergistic antiproliferative activity of peposertib in combination with doxorubicin, epirubicin and etoposide in multiple TNBC cell lines. Downstream analysis revealed the induction of ATM-dependent compensatory signaling and p53 pathway activation under combination treatment. These in vitro findings were substantiated by pronounced anti-tumor effects observed in mice bearing subcutaneously implanted tumors. We established a well-tolerated preclinical treatment regimen combining peposertib with pegylated liposomal doxorubicin (PLD) and demonstrated strong anti-tumor efficacy in cell-line-derived and patient-derived TNBC xenograft models in vivo. Taken together, our findings provide evidence that co-treatment with peposertib has the potential to enhance the efficacy of anthracycline/TOPO II-based chemotherapies, and it provides a promising strategy to improve treatment outcomes for TNBC patients.
Topics: Triple Negative Breast Neoplasms; Humans; Animals; Female; Mice; Topoisomerase II Inhibitors; Cell Line, Tumor; Xenograft Model Antitumor Assays; Doxorubicin; Drug Synergism; DNA-Activated Protein Kinase; Sulfones; Cell Proliferation; Antineoplastic Combined Chemotherapy Protocols; Polyethylene Glycols; Etoposide; DNA Topoisomerases, Type II; Epirubicin
PubMed: 38791158
DOI: 10.3390/ijms25105120 -
Science Advances May 2024DNA topoisomerase I can contribute to cancer genome instability. During catalytic activity, topoisomerase I forms a transient intermediate, topoisomerase I-DNA cleavage...
DNA topoisomerase I can contribute to cancer genome instability. During catalytic activity, topoisomerase I forms a transient intermediate, topoisomerase I-DNA cleavage complex (Top1cc) to allow strand rotation and duplex relaxation, which can lead to elevated levels of DNA-RNA hybrids and micronuclei. To comprehend the underlying mechanisms, we have integrated genomic data of Top1cc-triggered hybrids and DNA double-strand breaks (DSBs) shortly after Top1cc induction, revealing that Top1ccs increase hybrid levels with different mechanisms. DSBs are at highly transcribed genes in early replicating initiation zones and overlap with hybrids downstream of accumulated RNA polymerase II (RNAPII) at gene 5'-ends. A transcription factor IIS mutant impairing transcription elongation further increased RNAPII accumulation likely due to backtracking. Moreover, Top1ccs can trigger micronuclei when occurring during late G or early/mid S, but not during late S. As micronuclei and transcription-replication conflicts are attenuated by transcription factor IIS, our results support a role of RNAPII arrest in Top1cc-induced transcription-replication conflicts leading to DSBs and micronuclei.
Topics: Humans; DNA Breaks, Double-Stranded; DNA Replication; DNA Topoisomerases, Type I; Genomic Instability; R-Loop Structures; RNA Polymerase II; Transcription, Genetic
PubMed: 38787953
DOI: 10.1126/sciadv.adm8196 -
Journal of Chromatography. B,... Jun 2024DNA gyrase and topoisomerase IV play significant role in maintaining the correct structure of DNA during replication and they have been identified as validated targets...
Estimation of passive gastrointestinal absorption of new dual DNA gyrase and topoisomerase IV inhibitors using PAMPA and biopartitioning micellar chromatography and quantitative structure-retention relationship analysis.
DNA gyrase and topoisomerase IV play significant role in maintaining the correct structure of DNA during replication and they have been identified as validated targets in antibacterial drug discovery. Inadequate pharmacokinetic properties are responsible for many failures during drug discovery and their estimation in the early phase of this process maximizes the chance of getting useful drug candidates. Passive gastrointestinal absorption of a selected group of thirteen dual DNA gyrase and topoisomerase IV inhibitors was estimated using two in vitro tests - parallel artificial membrane permeability assay (PAMPA) and biopartitioning micellar chromatography (BMC). Due to good correlation between obtained results, passive gastrointestinal absorption of remaining ten compounds was estimated using only BMC. With this experimental setup, it was possible to identify compounds with high values of retention factors (k) and highest expected passive gastrointestinal absorption, and compounds with low values of k for which low passive gastrointestinal absorption is predicted. Quantitative structure-retention relationship (QSRR) modelling was performed by creating multiple linear regression (MLR), partial least squares (PLS) and support vector machines (SVM) models. Descriptors with the highest influence on retention factor were identified and their interpretation can be used for the design of new compounds with improved passive gastrointestinal absorption.
Topics: Quantitative Structure-Activity Relationship; Topoisomerase II Inhibitors; Gastrointestinal Absorption; Micelles; Linear Models; Membranes, Artificial; DNA Gyrase; Humans; DNA Topoisomerase IV
PubMed: 38776787
DOI: 10.1016/j.jchromb.2024.124158 -
RMD Open May 2024To untangle the association between smoking and systemic sclerosis (SSc).
OBJECTIVES
To untangle the association between smoking and systemic sclerosis (SSc).
METHODS
In the European Scleroderma Trials and Research cohort, the autoantibody status was compared between ever-smokers and never-smokers. Time until disease progression was assessed using Kaplan-Meier curves. Cox models were built to investigate the influence of smoking over 15 years of follow-up. All analyses were performed for the total cohort and stratified for sex and for positivity of anti-centromere (ACA) and anti-topoisomerase antibodies (ATA).
RESULTS
Overall, 12 314 patients were included in the study. Of these, 10 393 were women (84%), 4637 were ACA-positive (38%), 3919 were ATA-positive (32%) and 4271 (35%) were ever-smokers. In men, but not in women, smoking was associated with mortality (HR 1.63, 95% CI 1.23 to 2.16, p=0.001). Ever-smoking women were at higher risk for skin progression (HR 1.10, 95% CI 1.00 to 1.22, p=0.046) and for 'any organ progression' (HR 1.07, 95% CI 1.00 to 1.13, p=0.036). In women, 34% of never-smokers were ATA-positive compared with 21% of ever-smokers (p<0.001). In the group of ever-smokers, higher exposure rates, reflected by the number of pack-years (OR 0.98, 95% CI 0.97 to 0.99, p<0.001) and by smoking duration (OR 0.96, 95% CI 0.95 to 0.97, p<0.001), were associated with lower frequency of ATA. In ACA-positive patients, the risk of mortality (HR 1.29, 95% CI 1.02 to 1.63, p=0.033), cardiac involvement (HR 1.25, 95% CI 1.03 to 1.43, p=0.001), skin progression (HR 1.21, 95% CI 1.03 to 1.42, p=0.018) and 'any organ progression' (HR 1.14, 95% CI 1.05 to 1.24, p=0.002) was increased among smokers. In ATA-positive smoking patients, mortality (HR 1.40, 95% CI 1.10 to 1.78, p=0.006), skin progression (HR 1.19, 95% CI 1.03 to 1.37, p=0.020) digital ulcers (HR 1.17, 95% CI 1.02 to 1.34, p=0.029) and 'any organ progression' (HR 1.11, 95% CI 1.00 to 1.22, p=0.048) occurred more frequently.
CONCLUSIONS
Our stratified analysis demonstrates that smoking is associated with an increased risk for mortality in male SSc patients but not in women. Strikingly, smoking is associated with lower prevalence of ATA positivity, in particular in women. In both ATA-positive and ACA-positive patients, smoking is a risk factor for mortality, skin progression and 'any organ progression'.
Topics: Humans; Scleroderma, Systemic; Female; Male; Middle Aged; Smoking; Disease Progression; Adult; Proportional Hazards Models; Risk Factors; Autoantibodies; Aged; Kaplan-Meier Estimate; Cohort Studies
PubMed: 38772679
DOI: 10.1136/rmdopen-2024-004101 -
Biomedicine & Pharmacotherapy =... Jun 2024The molecular nanomachine, human DNA topoisomerase IIα, plays a crucial role in replication, transcription, and recombination by catalyzing topological changes in the...
The molecular nanomachine, human DNA topoisomerase IIα, plays a crucial role in replication, transcription, and recombination by catalyzing topological changes in the DNA, rendering it an optimal target for cancer chemotherapy. Current clinical topoisomerase II poisons often cause secondary tumors as side effects due to the accumulation of double-strand breaks in the DNA, spurring the development of catalytic inhibitors. Here, we used a dynamic pharmacophore approach to develop catalytic inhibitors targeting the ATP binding site of human DNA topoisomerase IIα. Our screening of a library of nature-inspired compounds led to the discovery of a class of 3-(imidazol-2-yl) morpholines as potent catalytic inhibitors that bind to the ATPase domain. Further experimental and computational studies identified hit compound 17, which exhibited selectivity against the human DNA topoisomerase IIα versus human protein kinases, cytotoxicity against several human cancer cells, and did not induce DNA double-strand breaks, making it distinct from clinical topoisomerase II poisons. This study integrates an innovative natural product-inspired chemistry and successful implementation of a molecular design strategy that incorporates a dynamic component of ligand-target molecular recognition, with comprehensive experimental characterization leading to hit compounds with potential impact on the development of more efficient chemotherapies.
Topics: Humans; DNA Topoisomerases, Type II; Topoisomerase II Inhibitors; Cell Line, Tumor; Drug Discovery; Antineoplastic Agents; Molecular Docking Simulation; Structure-Activity Relationship; Imidazoles; DNA Breaks, Double-Stranded; Antigens, Neoplasm
PubMed: 38772152
DOI: 10.1016/j.biopha.2024.116676 -
PloS One 2024Meningioma is the most common primary brain tumor and many studies have evaluated numerous biomarkers for their prognostic value, often with inconsistent results.... (Meta-Analysis)
Meta-Analysis
Meningioma is the most common primary brain tumor and many studies have evaluated numerous biomarkers for their prognostic value, often with inconsistent results. Currently, no reliable biomarkers are available to predict the survival, recurrence, and progression of meningioma patients in clinical practice. This study aims to evaluate the prognostic value of immunohistochemistry-based (IHC) biomarkers of meningioma patients. A systematic literature search was conducted up to November 2023 on PubMed, CENTRAL, CINAHL Plus, and Scopus databases. Two authors independently reviewed the identified relevant studies, extracted data, and assessed the risk of bias of the studies included. Meta-analyses were performed with the hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS). The risk of bias in the included studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool. A total of 100 studies with 16,745 patients were included in this review. As the promising markers to predict OS of meningioma patients, Ki-67/MIB-1 (HR = 1.03, 95%CI 1.02 to 1.05) was identified to associate with poor prognosis of the patients. Overexpression of cyclin A (HR = 4.91, 95%CI 1.38 to 17.44), topoisomerase II α (TOP2A) (HR = 4.90, 95%CI 2.96 to 8.12), p53 (HR = 2.40, 95%CI 1.73 to 3.34), vascular endothelial growth factor (VEGF) (HR = 1.61, 95%CI 1.36 to 1.90), and Ki-67 (HR = 1.33, 95%CI 1.21 to 1.46), were identified also as unfavorable prognostic biomarkers for poor RFS of meningioma patients. Conversely, positive progesterone receptor (PR) and p21 staining were associated with longer RFS and are considered biomarkers of favorable prognosis of meningioma patients (HR = 0.60, 95% CI 0.41 to 0.88 and HR = 1.89, 95%CI 1.11 to 3.20). Additionally, high expression of Ki-67 was identified as a prognosis biomarker for poor PFS of meningioma patients (HR = 1.02, 95%CI 1.00 to 1.04). Although only in single studies, KPNA2, CDK6, Cox-2, MCM7 and PCNA are proposed as additional markers with high expression that are related with poor prognosis of meningioma patients. In conclusion, the results of the meta-analysis demonstrated that PR, cyclin A, TOP2A, p21, p53, VEGF and Ki-67 are either positively or negatively associated with survival of meningioma patients and might be useful biomarkers to assess the prognosis.
Topics: Meningioma; Humans; Biomarkers, Tumor; Prognosis; Meningeal Neoplasms; DNA Topoisomerases, Type II; Ki-67 Antigen; Tumor Suppressor Protein p53; Vascular Endothelial Growth Factor A; Immunohistochemistry; Poly-ADP-Ribose Binding Proteins
PubMed: 38758750
DOI: 10.1371/journal.pone.0303337 -
Bioorganic Chemistry Jul 2024In our study, a series of quinazoline-1,2,3-triazole hybrids (14a-r) have been designed and synthesized as multi-target EGFR, VEGFR-2, and Topo II inhibitors. All...
In our study, a series of quinazoline-1,2,3-triazole hybrids (14a-r) have been designed and synthesized as multi-target EGFR, VEGFR-2, and Topo II inhibitors. All synthesized hybrids were assessed for their anticancer capacity. MTT assay revealed that compounds 14a, 14d, and 14k were the most potent hybrids against four cancer cell lines, HeLa, HePG-2, MCF-7, and HCT-116 at low micromolar range while exhibiting good selectivity against normal cell line WI-38. Sequentially, the three compounds were evaluated for EGFR, VEGFR-2, and Topo II inhibition. Compound 14d was moderate EGFR inhibitor (IC 0.103 µM) compared to Erlotinib (IC 0.049 µM), good VEGFR-2 inhibitor (IC 0.069 µM) compared to Sorafenib (IC 0.031 µM), and stronger Topo II inhibitor (IC 19.74 µM) compared to Etoposide (IC 34.19 µM) by about 1.7 folds. Compounds 14k and 14a represented strong inhibitory activity against Topo II with (IC 31.02 µM and 56.3 µM) respectively, compared to Etoposide. Additionally, cell cycle analysis and apoptotic induction were performed. Compound 14d arrested the cell cycle on HeLa at G2/M phase by 17.53 % and enhanced apoptosis by 44.08 %. A molecular Docking study was implemented on the three hybrids and showed proper binding interaction with EGFR, VEGFR-2, and Topo II active sites.
Topics: Humans; Antineoplastic Agents; Molecular Docking Simulation; Triazoles; Drug Screening Assays, Antitumor; Drug Design; Vascular Endothelial Growth Factor Receptor-2; Structure-Activity Relationship; ErbB Receptors; Cell Proliferation; Molecular Structure; DNA Topoisomerases, Type II; Dose-Response Relationship, Drug; Quinazolines; Protein Kinase Inhibitors; Apoptosis; Cell Line, Tumor; Topoisomerase II Inhibitors
PubMed: 38749114
DOI: 10.1016/j.bioorg.2024.107437 -
BioRxiv : the Preprint Server For... May 2024Repetitive satellite DNAs, divergent in nucleic-acid sequence and size across eukaryotes, provide a physical site for centromere assembly to orchestrate chromosome...
Repetitive satellite DNAs, divergent in nucleic-acid sequence and size across eukaryotes, provide a physical site for centromere assembly to orchestrate chromosome segregation during the cell cycle. These non-coding DNAs are transcribed by RNA polymerase (RNAP) II and the transcription has been shown to play a role in chromosome segregation, but a little is known about the regulation of centromeric transcription, especially in higher organisms with tandemly-repeated-DNA-sequence centromeres. Using RNA interference knockdown, chemical inhibition and AID/IAA degradation, we show that Topoisomerase I (TopI), not TopII, promotes the transcription of α-satellite DNAs, the main type of satellite on centromeres in human cells. Mechanistically, TopI localizes to centromeres, binds RNAP II and facilitates RNAP II elongation on centromeres. Interestingly, in response to DNA double-stranded breaks (DSBs) induced by chemotherapy drugs or CRSPR/Cas9, α-satellite transcription is dramatically stimulated in a DNA damage checkpoint-independent but TopI-dependent manner. These DSB-induced α-satellite RNAs were predominantly derived from the α-satellite high-order repeats of human centromeres and forms into strong speckles in the nucleus. Remarkably, TopI-dependent satellite transcription also exists in mouse 3T3 and S2 cells and in larval imaginal wing discs and tumor tissues. Altogether, our findings herein reveal an evolutionally conserved mechanism with TopI as a key player for the regulation of satellite transcription at both cellular and animal levels.
PubMed: 38746280
DOI: 10.1101/2024.05.03.592391