Search Results (3)

Background/Objectives: In the current medical era, Topoisomerase II is recognized as an essential enzyme that regulates DNA topology during critical biological processes such as DNA replication, transcription, and repair. This study aimed to design, synthesize, and biologically evaluate a new series of pyrazolo[3,4-b]pyridines (8a–g, 10a–g, and 12) as potential anticancer agents and Topoisomerase II inhibitors. Methods: The synthesized compounds were subjected to in vitro anticancer screening at the National Cancer Institute (NCI, USA). Active derivatives were further evaluated through a five-dose screening to determine their antiproliferative potency. Selected compounds were examined for their effects on leukemia cell lines (K562 and MV4-11), and mechanistic studies were performed to assess DNA damage, cell cycle distribution, and apoptosis-related protein modulation. Additionally, enzyme inhibition assays were conducted to determine Topoisomerase IIα (TOPIIα) inhibition. Results: Initial single-dose screening identified several active compounds, notably 8b, 8c, 8e, 8f, 10b, 10c, 10e, and 10f. Among these, compound 8c exhibited potent and broad-spectrum antiproliferative activity across the NCI cancer cell line panel, with a GI₅₀ MG-MID value of 1.33 µM (range: 0.54–2.08 µM). The synthesized molecules showed moderate to good anti-leukemic efficacy against K562 and MV4-11 cells. Mechanistic investigations revealed that compound 8c induced DNA damage and S-phase cell cycle arrest, leading to apoptosis as evidenced by the modulation of PARP-1, Bax, XIAP, and Caspases. Furthermore, target-based assays confirmed that compound 8c significantly inhibited the DNA relaxation activity of TOPIIα in a dose-dependent manner, comparable to etoposide. Conclusions: The study highlights compound 8c as a promising pyrazolo[3,4-b]pyridine derivative with potent antiproliferative activity and effective inhibition of Topoisomerase IIα. These findings suggest its potential as a lead scaffold for further optimization in anticancer drug development.. Full article

Type II topoisomerase (TOPII) is an enzyme that influences the topology of DNA. DNA breaks generated by TOPII may result in mutagenic or cytotoxic changes in cancer cells. In this study, we characterized interactions of TOPIIα with coffee extracts and individual chlorogenic acids (CHAs) from the extracts by performing isothermal titration calorimetry (ITC) and molecular docking (MD) simulations. The study showed that the highest affinity to TOPIIα was found in green coffee (ΔG = −38.23 kJ/mol) and monochlorogenic acids fraction of coffee extracts (ΔG = −35.80 kJ/mol), resulting from the high content of polyphenols, such as CHAs, which can bind to the enzyme in the active site. Coffee extracts and their fractions maintained a high affinity for TOPIIα after simulated digestion in the presence of probiotic bacteria. It can be concluded that coffee may be a potential TOPIIα inhibitor considered as a functional food for cancer prevention. Full article

Different types of canine lymphoma respond differently to chemotherapy and have different prognoses. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in dogs. Topoisomerase II alpha (TOPIIα) protein has been shown to be a proliferation marker associated with prognostic significance. The aim of the study was to determine the relationship between TOPIIα expression, mitotic count (MC), and Ki67 antigen index in DLBCL in dogs, taking into account the applicability of these parameters to select the chemotherapy protocol with emphasis on the use of anthracycline drugs. Samples of formalin-fixed paraffin-embedded lymph nodes from 34 dogs with DLBCL were immunohistochemically labelled with anti-TOPIIα and Ki67. The number of positive cells and the intensity of the reaction were taken into account in order to assess TOPIIα expression. MC was estimated in the hematoxylin and eosin-stained slides in the area of 2.37 mm². Positive association between TOPIIα and MC, but no association between TOPIIα and Ki67 was found. It can be concluded that the immunohistochemical determination of TOPIIα as a molecular target for drugs from the anthracycline group may be used in association with MC to establish a diagnostic-clinical protocol for selecting dogs with DLBCL for treatment with anthracycline drugs. Full article