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Journal of Enzyme Inhibition and... Aug 2023A new wave of dual Topo I/II inhibitors was designed and synthesised via the hybridisation of spirooxindoles and pyrimidines. selenium nanoparticles (SeNPs) for some...
A new wave of dual Topo I/II inhibitors was designed and synthesised via the hybridisation of spirooxindoles and pyrimidines. selenium nanoparticles (SeNPs) for some derivatives were synthesised. The targets and the SeNP derivatives were examined for their cytotoxicity towards five cancer cell lines. The inhibitory potencies of the best members against Topo I and Topo II were also assayed besides their DNA intercalation abilities. Compound exhibited the best inhibition against Topo I and Topo II enzymes with IC of 0.042 and 1.172 μM, respectively. The ability of compound to arrest the cell cycle and induce apoptosis was investigated. It arrested the cell cycle in the A549 cell at the S phase and prompted apoptosis by 41.02% vs. 23.81% in the control. studies were then performed to study the possible binding interactions between the designed members and the target proteins.
Topics: Selenium; Intercalating Agents; Cell Cycle; DNA Topoisomerases, Type II; Nanoparticles; DNA
PubMed: 37592917
DOI: 10.1080/14756366.2023.2242714 -
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 -
European Journal of Medicinal Chemistry Nov 2023Although the great effectiveness of doxorubicin (Dox) in the treatment of many types of tumors, it showed limited effectiveness against the head and neck squamous cell...
Novel fused imidazotriazines acting as promising top. II inhibitors and apoptotic inducers with greater selectivity against head and neck tumors: Design, synthesis, and biological assessments.
Although the great effectiveness of doxorubicin (Dox) in the treatment of many types of tumors, it showed limited effectiveness against the head and neck squamous cell carcinoma (HNSCC) subtype which is attributed to its reported multiple drug resistance (MDR). In the current study, we considered the essential pharmacophoric features of Dox as an effective Top. II inhibitor and sought to develop a novel set of imidazo[1,2-a] [1,3,5]triazin-2-amines (2a-2p) as a suggested anticancer option that could intercalate the DNA base pairs. We evaluated the % inhibition of the newly synthesized compounds on thirteen cancer cell lines and the analysis of structure-activity relationships revealed that the human head and neck cancer cell line (HNO97) was the most sensitive to their growth inhibition effect. Then, the IC values were recorded against the most sensitive cancer cell lines (HNO97, MDA-MB-231, and HEPG2), and compared to the normal cell line OEC (human oral epithelial cells). Compounds 2f and 2g showed very strong activities against HNO97 with IC values of (4 ± 1 and 3 ± 1.5 μg/mL), respectively, compared to that of Dox (9 ± 1.6 μg/mL). Next, a quantitative determination of human DNA Top. II concentrations in the most sensitive cell line (HNO97) were recorded for the most active anticancer derivatives. Again, compound 2f showed a superior Top. II inhibition with 87.86% compared to that of Dox (86.44%), while compound 2g achieved an inhibition of 81.37% which was close to the effect of Dox. To further investigate their effects on cell cycle progression and apoptosis induction in HNO97 cells, both 2f and 2g were selected for analysis. Both candidates arrested cell cycle progression at both the S and G2-M phases, as well as increased the early and late apoptosis phase ratios. Besides, both 2f and 2g were subjected to protein expression analysis of apoptosis-related genes (p53, BAX, IL-6, and BCL2). Moreover, the antioxidant effect of 2f and 2g was evaluated by measuring GSH, MDA, and NO markers in HNO97 cells. Furthermore, molecular docking for the newly designed tricyclic derivatives against both the Top. II and DNA double helix was carried out.
Topics: Humans; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Drug Screening Assays, Antitumor; Head and Neck Neoplasms; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship; Triazines; Topoisomerase II Inhibitors
PubMed: 37482023
DOI: 10.1016/j.ejmech.2023.115661 -
International Journal of Molecular... Jul 2023Novel bacterial topoisomerase inhibitors (NBTIs) are an emerging class of antibacterials that target gyrase and topoisomerase IV. A hallmark of NBTIs is their ability to...
Novel bacterial topoisomerase inhibitors (NBTIs) are an emerging class of antibacterials that target gyrase and topoisomerase IV. A hallmark of NBTIs is their ability to induce gyrase/topoisomerase IV-mediated single-stranded DNA breaks and suppress the generation of double-stranded breaks. However, a previous study reported that some dioxane-linked amide NBTIs induced double-stranded DNA breaks mediated by gyrase. To further explore the ability of this NBTI subclass to increase double-stranded DNA breaks, we examined the effects of OSUAB-185 on DNA cleavage mediated by gyrase and topoisomerase IV. OSUAB-185 induced single-stranded and suppressed double-stranded DNA breaks mediated by gyrase. However, the compound stabilized both single- and double-stranded DNA breaks mediated by topoisomerase IV. The induction of double-stranded breaks does not appear to correlate with the binding of a second OSUAB-185 molecule and extends to fluoroquinolone-resistant topoisomerase IV, as well as type II enzymes from other bacteria and humans. The double-stranded DNA cleavage activity of OSUAB-185 and other dioxane-linked NBTIs represents a paradigm shift in a hallmark characteristic of NBTIs and suggests that some members of this subclass may have alternative binding motifs in the cleavage complex.
Topics: Humans; DNA Topoisomerase IV; Neisseria gonorrhoeae; DNA Gyrase; DNA Breaks, Double-Stranded; Topoisomerase II Inhibitors
PubMed: 37569485
DOI: 10.3390/ijms241512107 -
Journal of Enzyme Inhibition and... Dec 2023In the present study, 5-arylidene rhodanine derivatives , -glucosylation rhodanine , -glucosylation rhodanine , -glucoside rhodanine and -glucosylation 5-arylidene...
In the present study, 5-arylidene rhodanine derivatives , -glucosylation rhodanine , -glucosylation rhodanine , -glucoside rhodanine and -glucosylation 5-arylidene rhodanines were synthesised and screened for cytotoxicity against a panel of cancer cells with investigating the effective molecular target and mechanistic cell death. The anomers were separated by flash column chromatography and their configurations were assigned by NMR spectroscopy. The stable structures of the compounds under study were modelled on a molecular level, and DFT calculations were carried out at the B3LYP/6-31 + G (d,p) level to examine their electronic and geometric features. A good correlation between the quantum chemical descriptors and experimental observations was found. Interestingly, compound induced potent cytotoxicity against MCF-7, HepG2 and A549 cells, with IC values of 11.7, 0.21, and 1.7 µM, compared to Dox 7.67, 8.28, and 6.62 µM, respectively. For the molecular target, compound exhibited topoisomerase II inhibition and DNA intercalation with IC values of 6.9 and 19.6 µM, respectively compared to Dox (IC = 9.65 and 31.27 µM). Additionally, compound treatmnet significantly activated apoptotic cell death in HepG2 cells by 80.7-fold, it induced total apoptosis by 34.73% (23.07% for early apoptosis, 11.66% for late apoptosis) compared to the untreated control group (0.43%) arresting the cell population at the -phase by 49.6% compared to control 39.15%. Finally, compound upregulated the apoptosis-related genes, while it inhibted the Bcl-2 expression. Hence, glucosylated rhodanines may serve as a promising drug candidates against cancer with promising topoisomerase II and DNA intercalation.
Topics: Molecular Structure; Rhodanine; Antineoplastic Agents; Drug Screening Assays, Antitumor; Topoisomerase II Inhibitors; DNA Topoisomerases, Type II; DNA; Structure-Activity Relationship; Cell Proliferation; Apoptosis
PubMed: 36629439
DOI: 10.1080/14756366.2022.2163996 -
Journal of Ethnopharmacology Dec 2023The search for effective herbal medicines for complementary treatments is on the rise due to the high incidence of recurrence and mortality rate in human oral cancer....
ETHNOPHARMACOLOGICAL RELEVANCE
The search for effective herbal medicines for complementary treatments is on the rise due to the high incidence of recurrence and mortality rate in human oral cancer. Rhinacanthus nasutus KURZ., an annual herb found mostly in Southeast Asia including Thailand, has been wildly used as a traditional folk medicine for the treatment of several diseases including cancer. However, the anti-cancer effect of Rhinacanthin-C (Rh-C) as a major naphthoquinone compound found in R. nasutus and the underlying mechanism of its action on human oral cancer cells remain unknown.
AIM OF THE STUDY
To investigate the anti-cancer mechanism of Rh-C extracted from R. nasutus in human oral cancer cells.
MATERIALS AND METHODS
The anti-proliferative effect of Rh-C on human oral squamous cell carcinoma (HSC4) was determined and compared to normal oral cells (human gingival fibroblasts, HGF, and normal oral keratinocytes, NOK) using the SRB colorimetric method. The molecular mechanism of Rh-C was explored using flow cytometry, colorimetric assay, in vitro human topoisomerase II assay, and Western blotting.
RESULTS
Rh-C displayed a time- and concentration-dependent growth inhibition on HSC4 and was much less effective on both tested normal oral cells. Rh-C inhibited Akt phosphorylation whereas over-activated p38 MAPK phosphorylation in HSC4 but not in HGF. Rh-C also inhibited topoisomerase II activity. As a result, the cell cycle was arrested in S-phase as the expression of CDK1/2 and Cyclin A2 was decreased. Eventually, the induction of HSC4 cell apoptosis was mediated by increased caspase 3 activity.
CONCLUSIONS
Rh-C isolated from R. nasutus possesses anti-cancer properties on human oral cancer cells by causing the S arrest and the apoptotic induction via modulating Akt/p38 signaling pathways. The results provide molecular bases for further developing Rh-C as a potential drug candidate or a complementary treatment for oral cancer.
Topics: Humans; Mouth Neoplasms; Proto-Oncogene Proteins c-akt; Carcinoma, Squamous Cell; Signal Transduction; Naphthoquinones; Apoptosis; Cell Line, Tumor
PubMed: 37348799
DOI: 10.1016/j.jep.2023.116813 -
Journal of Enzyme Inhibition and... Dec 2023Topoisomerases II are ubiquitous enzymes with significant genotoxic effects in many critical DNA processes. Additionally, epidermal growth factor receptor (EGFR) plays...
Novel topoisomerase II/EGFR dual inhibitors: design, synthesis and docking studies of naphtho[2',3':4,5]thiazolo[3,2-]pyrimidine hybrids as potential anticancer agents with apoptosis inducing activity.
Topoisomerases II are ubiquitous enzymes with significant genotoxic effects in many critical DNA processes. Additionally, epidermal growth factor receptor (EGFR) plays pivotal role in tumour growth and angiogenesis. A novel series of naphtho[2',3':4,5]thiazolo[3,2-]pyrimidine hybrids have been designed, synthesised and evaluated for their topo IIα/EGFR inhibitory and apoptotic inducer activities. Cytotoxicity of the synthesised hybrids was evaluated against MCF-7, A549 and HCT-116 cell lines. Of the synthesised hybrids, , and experienced superior cytotoxic activity compared to doxorubicin and erlotinib against the tested cancer cells. The molecular mechanism of these hybrids revealed their ability to successfully inhibit topo IIα and EGFR activities in micromolar concentration and may serve as topo II catalytic inhibitor. Moreover, these hybrids significantly arrested cell cycle at G2/M phase together with increased p53, caspae-7, caspase-9 levels and Bax/Bcl-2 ratio. The synthesised hybrids showed efficient binding pattern in molecular docking study and have acceptable drug likeness characters.
Topics: Molecular Docking Simulation; Antineoplastic Agents; DNA Topoisomerases, Type II; ErbB Receptors; Apoptosis; Pyrimidines; Topoisomerase II Inhibitors; Drug Screening Assays, Antitumor; Cell Proliferation; Structure-Activity Relationship; Cell Line, Tumor
PubMed: 37165800
DOI: 10.1080/14756366.2023.2205043 -
Nucleic Acids Research Apr 2024RNA-binding proteins emerge as effectors of the DNA damage response (DDR). The multifunctional non-POU domain-containing octamer-binding protein NONO/p54nrb marks...
RNA-binding proteins emerge as effectors of the DNA damage response (DDR). The multifunctional non-POU domain-containing octamer-binding protein NONO/p54nrb marks nuclear paraspeckles in unperturbed cells, but also undergoes re-localization to the nucleolus upon induction of DNA double-strand breaks (DSBs). However, NONO nucleolar re-localization is poorly understood. Here we show that the topoisomerase II inhibitor etoposide stimulates the production of RNA polymerase II-dependent, DNA damage-inducible antisense intergenic non-coding RNA (asincRNA) in human cancer cells. Such transcripts originate from distinct nucleolar intergenic spacer regions and form DNA-RNA hybrids to tether NONO to the nucleolus in an RNA recognition motif 1 domain-dependent manner. NONO occupancy at protein-coding gene promoters is reduced by etoposide, which attenuates pre-mRNA synthesis, enhances NONO binding to pre-mRNA transcripts and is accompanied by nucleolar detention of a subset of such transcripts. The depletion or mutation of NONO interferes with detention and prolongs DSB signalling. Together, we describe a nucleolar DDR pathway that shields NONO and aberrant transcripts from DSBs to promote DNA repair.
Topics: Humans; DNA Breaks, Double-Stranded; DNA-Binding Proteins; Etoposide; RNA Precursors; Transcription Factors; DNA; RNA-Binding Proteins
PubMed: 38224452
DOI: 10.1093/nar/gkae022 -
Journal of Enzyme Inhibition and... Dec 2023A series of novel ciprofloxacin (CP) derivatives substituted at the N-4 position with biologically active moieties were designed and synthesised. 14 compounds were 1.02-...
A series of novel ciprofloxacin (CP) derivatives substituted at the N-4 position with biologically active moieties were designed and synthesised. 14 compounds were 1.02- to 8.66-fold more potent than doxorubicin against T-24 cancer cells. Ten compounds were 1.2- to 7.1-fold more potent than doxorubicin against PC-3 cancer cells. The most potent compounds , , , , , and showed significant Topo II inhibitory activity (83-90% at 100 μM concentration). Compounds , , and were 1.01- to 2.32-fold more potent than doxorubicin. Compounds and induced apoptosis in T-24 (16.8- and 20.1-fold, respectively compared to control). This evidence was supported by an increase in the level of apoptotic caspase-3 (5.23- and 7.6-fold, sequentially). Both compounds arrested the cell cycle in the S phase in T-24 cancer cells while in PC-3 cancer cells the two compounds arrested the cell cycle in the G1 phase. Molecular docking simulations of compounds and into the Topo II active site rationalised their remarkable Topo II inhibitory activity.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Ciprofloxacin; DNA Topoisomerases, Type II; Dose-Response Relationship, Drug; Doxorubicin; Drug Screening Assays, Antitumor; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship
PubMed: 36305290
DOI: 10.1080/14756366.2022.2136172 -
Bioorganic & Medicinal Chemistry Letters Oct 2023Mitoxantrone (MX) is a robust chemotherapeutic with well-characterized applications in treating certain leukemias and advanced breast and prostate cancers. The canonical...
Mitoxantrone (MX) is a robust chemotherapeutic with well-characterized applications in treating certain leukemias and advanced breast and prostate cancers. The canonical mechanism of action associated with MX is its ability to intercalate DNA and inhibit topoisomerase II, giving it the designation of a topoisomerase II poison. Years after FDA approval, investigations have unveiled novel protein-binding partners, such as methyl-CpG-binding domain protein (MBD2), PIM1 serine/threonine kinase, RAD52, and others that may contribute to the therapeutic profile of MX. Moreover, recent proteomic studies have revealed MX's ability to modulate protein expression, illuminating the complex cellular interactions of MX. Although mechanistically relevant, the differential expression across the proteome does not address the direct interaction with potential binding partners. Identification and characterization of these MX-binding cellular partners will provide the molecular basis for the alternate mechanisms that influence MX's cytotoxicity. Here, we describe the design and synthesis of a MX-biotin probe (MXP) and negative control (MXP-NC) that can be used to define MX's cellular targets and expand our understanding of the proteome-wide profile for MX. In proof of concept studies, we used MXP to successfully isolate a recently identified protein-binding partner of MX, RAD52, in a cell lysate pulldown with streptavidin beads and western blotting.
Topics: Humans; Male; DNA Topoisomerases, Type II; DNA-Binding Proteins; Mitoxantrone; Prostatic Neoplasms; Proteome; Proteomics; Molecular Probes; Breast Neoplasms; Female
PubMed: 37669721
DOI: 10.1016/j.bmcl.2023.129465