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The Clinical Respiratory Journal Dec 2023Although lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) have different pathological and clinical features, they may share common driver genes. It was...
BACKGROUND
Although lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) have different pathological and clinical features, they may share common driver genes. It was found that lipid levels can be used for early diagnosis of NSCLC; however, the relationship between driver genes and genes regulating lipid metabolism and their relationship with patient prognosis needs further investigation.
METHODS
Genes whose expression was up- or down-regulated in both LUAD and LUSC were identified using the GEO database. Online tools like GEPIA 2, PrognoScan, UALCAN, and TIMER2.0 were used to investigate the association of these gene expressions with the patient's prognosis and lipid regulatory genes. The association between clinical lipid levels and the risk of LUAD and LUSC was analyzed by using a multiple logistic regression model.
RESULTS
Topoisomerase II alpha (TOP2A) and alcohol dehydrogenase 1B (ADH1B) were identified as the only genes up- and down-regulated in both LUAD and LUSC. TOP2A and ADH1B expression levels significantly correlated with the patient's gender, age, individual cancer stage, histological subtype, nodal metastasis status, and TP53 mutation status. Additionally, only LUAD patients with higher TOP2A or lower ADH1B expressions displayed poor overall and relapse-free survival rates. Moreover, TOP2A levels exhibited a negative correlation with adipose triglyceride lipase (ATGL) and ATP-binding cassette transporter A1 (ABCA1) in both LUAD and LUSC. However, ADH1B showed inverse associations with the above-mentioned genes when compared to TOP2A expressions in both LUAD and LUSC. Furthermore, elevated triglyceride (OR = 1.59; 95% CI = 1.01 to 2.49; P < 0.05) and total cholesterol (OR = 2.45; 95% CI = 1.08 to 5.57; P < 0.05) levels might increase the risk of LUAD.
CONCLUSIONS
TOP2A and ADH1B can be used as diagnostic markers for LUAD and LUSC, but only as independent prognostic factors for LUAD, and may be involved in lipid metabolism in LUAD patients but not in LUSC. Thus, combining genetic diagnostics with lipid panel tests might be an effective method for an early diagnosis and improved prognosis of LUAD.
Topics: Humans; Adenocarcinoma of Lung; Alcohol Dehydrogenase; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; DNA Topoisomerases, Type II; Lipids; Lung Neoplasms; Neoplasm Recurrence, Local; Prognosis
PubMed: 37985446
DOI: 10.1111/crj.13717 -
Frontiers in Oncology 2023Neoadjuvant anthracycline-based chemotherapy (NAC) is a major regimen for the treatment of local advanced breast cancer (LABC), while resistance to NAC remains a...
Evaluating the expression of heat shock protein 27 and topoisomerase II α in a retrospective cohort of patients diagnosed with locally advanced breast cancer and treated with neoadjuvant anthracycline-based chemotherapies.
BACKGROUND
Neoadjuvant anthracycline-based chemotherapy (NAC) is a major regimen for the treatment of local advanced breast cancer (LABC), while resistance to NAC remains a paramount clinical obstacle. To investigate the role of heat shock protein 27 (Hsp27) and/or topoisomerase IIα (TopoIIα) in LABC patients treated with NAC, we performed this retrospective study.
METHODS
Associations of Hsp27 transcripts with clinic-pathological characteristics, survival and drug response were investigated in public databases. Hsp27-related genes were identified, followed by functional enrichment analyses. Besides, two protein-protein interaction networks were built. Then, tumors from 103 patients who were diagnosed with LABC and received NAC were collected, and Hsp27 and TopoIIα were examined by Immunohistochemistry (IHC). Chi-square or Fisher's exact tests were performed, as well as survival analyses.
RESULTS
Either at the transcriptional level in public databases or at the protein level tested by IHC, a high level of Hsp27 was associated with aggressive tumor characteristics such as lymph node invasion and chemotherapy resistance. Hsp27-related genes mostly involved in the metabolic pathway and the gamete generation biological process. An elevated Hsp27 indicated a poor prognosis in patients with breast cancer (log-rank test = 0.002 and 0.004 for disease-free survival [DFS] and overall survival [OS], respectively), while it might not be an independent predictor. Of note, tumors with high TopoIIα expression (TopoIIα+) was less likely to express Hsp27 (Hsp27+), in contrast to those with TopoIIα negativity (31.1% vs. 86.2%, <0.001), and survival analyses revealed that patients with Hsp27+ and TopoIIα- tumors had a significantly lower DFS and OS (log-rank test < 0.001 and 0.001, respectively), in contrast to the other three groups.
CONCLUSIONS
Hsp27 was associated with aggressive breast cancers and more predictable for the prognosis of LABC patients treated with NAC when concomitantly considering TopoIIα expression.
PubMed: 37675221
DOI: 10.3389/fonc.2023.1067179 -
Technology in Cancer Research &... 2024The development of 1,8-naphthalimide derivatives as cell probes, DNA targeting agents, and anti-tumor drugs is one of the research hotspots in the field of medicine.... (Review)
Review
The development of 1,8-naphthalimide derivatives as cell probes, DNA targeting agents, and anti-tumor drugs is one of the research hotspots in the field of medicine. Naphthalimide compounds are a kind of DNA embedder, which can change the topological structure of DNA by embedding in the middle of DNA base pairs, and then affect the recognition and action of topoisomerase on DNA. Aminofide and mitonafide are the first 2 drugs to undergo clinical trials. They have good DNA insertion ability, can embed DNA double-stranded structure, and induce topoisomerase II to cut part of pBR322DNA, but not yet entered the market due to their toxicity. In this paper, the design and structure-activity relationship of mononaphthalimide and bisaphthalimide compounds were studied, and the relationship between the structure of naphthalimide and anti-tumor activity was analyzed and discussed. It was found that a variety of structural modifications were significant in improving anti-tumor activity and reducing toxicity.
Topics: Humans; Naphthalimides; Structure-Activity Relationship; Neoplasms; DNA; Antineoplastic Agents; Cell Line, Tumor
PubMed: 38225189
DOI: 10.1177/15330338231225861 -
ACS Infectious Diseases Apr 2024Antimicrobial resistance is a global threat to human health. Therefore, efforts have been made to develop new antibacterial agents that address this critical medical...
Antimicrobial resistance is a global threat to human health. Therefore, efforts have been made to develop new antibacterial agents that address this critical medical issue. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibacterial in clinical development. Recently, phase III clinical trials for gepotidacin treatment of uncomplicated urinary tract infections caused by uropathogens, including , were stopped for demonstrated efficacy. Because of the clinical promise of gepotidacin, it is important to understand how the compound interacts with its cellular targets, gyrase and topoisomerase IV, from . Consequently, we determined how gyrase and topoisomerase IV mutations in amino acid residues that are involved in gepotidacin interactions affect the susceptibility of cells to the compound and characterized the effects of gepotidacin on the activities of purified wild-type and mutant gyrase and topoisomerase IV. Gepotidacin displayed well-balanced dual-targeting of gyrase and topoisomerase IV in cells, which was reflected in a similar inhibition of the catalytic activities of these enzymes by the compound. Gepotidacin induced gyrase/topoisomerase IV-mediated single-stranded, but not double-stranded, DNA breaks. Mutations in GyrA and ParC amino acid residues that interact with gepotidacin altered the activity of the compound against the enzymes and, when present in both gyrase and topoisomerase IV, reduced the antibacterial activity of gepotidacin against this mutant strain. Our studies provide insights regarding the well-balanced dual-targeting of gyrase and topoisomerase IV by gepotidacin in .
Topics: Acenaphthenes; Amino Acids; Anti-Bacterial Agents; DNA Gyrase; DNA Topoisomerase IV; Escherichia coli; Heterocyclic Compounds, 3-Ring
PubMed: 38606465
DOI: 10.1021/acsinfecdis.3c00346 -
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 -
Molecular Therapy. Oncology Mar 2024The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic...
The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic stress by targeting protein degradation with proteasome inhibitors (PIs) has revolutionized the treatment of MM. However, resistance to PIs is inevitable and represents an ongoing clinical challenge. Our first-in-human study of the selective inhibitor of RNA polymerase I transcription of ribosomal RNA genes, CX-5461, has demonstrated a potential signal for anti-tumor activity in three of six heavily pre-treated MM patients. Here, we show that CX-5461 has potent anti-myeloma activity in PI-resistant MM preclinical models and . In addition to inhibiting ribosome biogenesis, CX-5461 causes topoisomerase II trapping and replication-dependent DNA damage, leading to G2/M cell-cycle arrest and apoptotic cell death. Combining CX-5461 with PI does not further enhance the anti-myeloma activity of CX-5461 . In contrast, CX-5461 shows synergistic interaction with the histone deacetylase inhibitor panobinostat in both the Vk∗MYC and the 5T33-KaLwRij mouse models of MM by targeting ribosome biogenesis and protein synthesis through distinct mechanisms. Our findings thus provide strong evidence to facilitate the clinical development of targeting the ribosome to treat relapsed and refractory MM.
PubMed: 38596309
DOI: 10.1016/j.omton.2024.200771 -
Mini Reviews in Medicinal Chemistry 2024Antibiotic or antimicrobial resistance is an urgent global public health threat that occurs when bacterial or fungal infections do not respond to the drug regimen... (Review)
Review
Antibiotic or antimicrobial resistance is an urgent global public health threat that occurs when bacterial or fungal infections do not respond to the drug regimen designed to treat these infections. As a result, these microbes are not evaded and continue to grow. Antibiotic resistance against natural and already-known antibiotics like Ciprofloxacin and Novobiocin can be overcome by developing an agent that can act in different ways. The success of agents like Zodiflodacin and Zenoxacin in clinical trials against DNA gyrase inhibitors that act on different sites of DNA gyrase has resulted in further exploration of this target. However, due to the emergence of bacterial resistance against these targets, there is a great need to design agents that can overcome this resistance and act with greater efficacy. This review provides information on the synthetic and natural DNA gyrase inhibitors that have been developed recently and their promising potential for combating antimicrobial resistance. The review also presents information on molecules that are in clinical trials and their current status. It also analysed the SAR studies and mechanisms of action of enlisted agents.
Topics: Topoisomerase II Inhibitors; DNA Gyrase; Humans; Anti-Bacterial Agents; Bacteria; Microbial Sensitivity Tests; Structure-Activity Relationship
PubMed: 37909434
DOI: 10.2174/0113895575264264230921080718 -
Chemistry & Biodiversity May 2024Currently, natural products are one of the priceless options for finding novel chemical pharmaceutical entities. Ellipticine is a naturally occurring alkaloid isolated... (Review)
Review
Currently, natural products are one of the priceless options for finding novel chemical pharmaceutical entities. Ellipticine is a naturally occurring alkaloid isolated from the leaves of Ochrosia elliptica Labill. Ellipticine and its derivatives are characterized by multiple biological activities. The purpose of this review was to provide a critical and systematic assessment of ellipticine and its derivatives as bioactive molecules over the last 60 years. Publications focused mainly on the total synthesis of alkaloids of this type without any evaluation of bioactivity have been excluded. We have reviewed papers dealing with the synthesis, bioactivity evaluation and mechanism of action of ellipticine and its derivatives. It was found that ellipticine and its derivatives showed cytotoxicity, antimicrobial ability, and anti-inflammatory activity, among which cytotoxicity toward cancer cell lines was the most investigated aspect. The inhibition of DNA topoisomerase II was the most relevant mechanism for cytotoxicity. The PI3K/AKT pathway, p53 pathway, and MAPK pathway were also closely related to the antiproliferative ability of these compounds. In addition, the structure-activity relationship was deduced, and future prospects were outlined. We are confident that these findings will lay a scientific foundation for ellipticine-based drug development, especially for anticancer agents.
Topics: Ellipticines; Humans; Structure-Activity Relationship; Antineoplastic Agents; Cell Proliferation; Anti-Inflammatory Agents; Anti-Infective Agents; Molecular Structure; Animals; Antineoplastic Agents, Phytogenic
PubMed: 38433548
DOI: 10.1002/cbdv.202400210 -
Journal of Inorganic Biochemistry Sep 2023Two new ruthenium(II) complexes [Ru(dip)(PPβC)]PF (Ru1, dip = 4,7-diphenyl-1,10-phenanthroline,...
Two new ruthenium(II) complexes [Ru(dip)(PPβC)]PF (Ru1, dip = 4,7-diphenyl-1,10-phenanthroline, PPβC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide) and [Ru(phen)(PPβC)]PF (Ru2, phen = 1, 10-phenanthroline) with β-carboline derivative PPβC as the primary ligand, were designed and synthesized. Ru1 and Ru2 displayed higher antiproliferative activity than cisplatin against the test cancer cells, with IC values ranging from 0.5 to 3.6 μM. Moreover, Ru1 and Ru2 preferentially accumulated in mitochondria and caused a series of changes in mitochondrial events, including the depolarization of mitochondrial membrane potential, the damage of mitochondrial DNA, the depletion of cellular ATP, and the elevation of intracellular reactive oxygen species levels. Then, it induced caspase-3/7-mediated A549 cell apoptosis. More importantly, both complexes could act as topoisomerase I catalytic inhibitors to inhibit mitochondrial DNA synthesis. Accordingly, the developed Ru(II) complexes hold great potential to be developed as novel therapeutics for cancer treatment.
Topics: Humans; A549 Cells; Ruthenium; Antineoplastic Agents; Mitochondria; Apoptosis; DNA, Mitochondrial; Coordination Complexes; Reactive Oxygen Species; Cell Line, Tumor
PubMed: 37348172
DOI: 10.1016/j.jinorgbio.2023.112295 -
Toxicon : Official Journal of the... Feb 2024Bufadienolides are digitalis-like aglycones mainly found in skin secretions of toads. Among their biological properties, the mechanisms of antiproliferative action on...
Bufadienolides are digitalis-like aglycones mainly found in skin secretions of toads. Among their biological properties, the mechanisms of antiproliferative action on tumor cells remain unclear for many compounds, including against leukemia cells. Herein, it was evaluated the mechanisms involved in the antiproliferative and genotoxic actions of hellebrigenin on tumor cell lines and in silico capacity to inhibit the human topoisomerase IIa enzyme. Firstly, its cytotoxic action was investigated by colorimetric assays in human tumor and peripheral blood mononuclear cells (PBMC). Next, biochemical and morphological studies were detailed by light microscopy (trypan blue dye exclusion), immunocytochemistry (BrdU uptake), flow cytometry and DNA/chromosomal damages (Cometa and aberrations). Finally, computational modelling was used to search for topoisomerase inhibition. Hellebrigenin reduced proliferation, BrdU incorporation, viability, and membrane integrity of HL-60 leukemia cells. Additionally, it increased G/M arrest, internucleosomal DNA fragmentation, mitochondrial depolarization, and phosphatidylserine externalization in a concentration-dependent manner. In contrast to doxorubicin, hellebrigenin did not cause DNA strand breaks in HL-60 cell line and lymphocytes, and it interacts with ATPase domain residues of human topoisomerase IIa, generating a complex of hydrophobic and van der Waals interactions and hydrogen bonds. So, hellebrigenin presented potent anti-leukemic activity at concentrations as low as 0.06 μM, a value comparable to the clinical anticancer agent doxorubicin, and caused biochemical changes suggestive of apoptosis without genotoxic/clastogenic-related action, but it probably triggers catalytic inhibition of topoisomerase II. These findings also emphasize toad steroid toxins as promising lead antineoplasic compounds with relatively low cytotoxic action on human normal cells.
Topics: Humans; Leukocytes, Mononuclear; Bromodeoxyuridine; DNA Damage; Antineoplastic Agents; Bufanolides; HL-60 Cells; Apoptosis; Leukemia; DNA; Doxorubicin
PubMed: 38160738
DOI: 10.1016/j.toxicon.2023.107591