Search Results (745)

A novel series of thiazole chalcone/ciprofloxacin hybrids were synthesized and screened for their anticancer activity against NCI-60 cancer cell lines, USA. Interestingly, compounds 4b and 4d exhibited potent antiproliferative activities, particularly against leukemia HL-60, RPMI-8226, and colon HCT-116 cells, with IC₅₀ values of 0.3–3.70 µM. Importantly, compounds 4b and 4d exhibited enhanced selectivity for cancer cells relative to doxorubicin with IC₅₀ values of 26.80, 41.20, and 19.80 µM, respectively. Mechanistic investigations revealed that compounds 4b and 4d inhibited topoisomerases (Topo) I/IIβ activity, being fourfold and twofold more effective than untreated controls, respectively. Furthermore, these compounds induced G1 phase cell cycle arrest and promoted apoptosis, which likely explain their potent anticancer properties. In depth, compound 4d increased the relative gene expression of pro-apoptotic Bax (5.58-fold) and caspase-3 (10.86-fold) as well as the initiator caspase-9 (4.2-fold), and reduced the relative gene expression of Bcl-2. Therefore, ciprofloxacin/thiazole chalcone derivatives, particularly 4b and 4d, may serve as promising candidates for the development of antitumor agents. Full article

Anthraquinones are molecules with numerous biological properties that can act as DNA intercalators and topoisomerase IIa inhibitors. In this work, the development of technetium-99m radiotracers was pursued via the technetium-tricarbonyl “2 + 1” mixed-ligand approach, fac-[^99mTc][Tc^I(CO)₃(NN′)(N)]⁺, with a (N,N′) bidentate chelator and a N co-ligand. In one approach, the ligands used were 2,2′-bipyridine (bpy) and N-functionalized-imidazole, where imidazole was conjugated to an anthraquinone moiety. In the other approach, 2-picolylamine and imidazole were used as the mixed-ligand system, where picolylamine was conjugated to an anthraquinone moiety. The synthesis of the ligands was achieved by reaction of 2-picolylamine with a suitably functionalized anthraquinone (Aqpa) or anthrapyrazole (Appa) and imidazole with a suitably functionalized anthraquinone (Aqim). The rhenium reference compounds, fac-[Re^I(CO)₃(bpy)(Aqim)]⁺ with bpy as a bidentate chelator and fac-[Re^I(CO)₃(Aqpa or Appa)(Im)]⁺, with imidazole (Im) as a co-ligand, were synthesized and characterized with spectroscopic methods. The radiotracer technetium-99m complexes fac-[^99mTc][Tc(CO)₃(bpy)(Aqim)]⁺ and fac-[^99mTc][Tc(CO)₃(Aqpa or Appa)(Im)]⁺ were prepared and characterized with standard methods. The purified radiotracers displayed high stability (≥90%) after incubation 24 h in 1 mM L-histidine or rat plasma. The tracers’ cell uptake was evaluated in vitro in CT-26 cells, and their pharmacokinetic properties and tumor uptake were evaluated in vivo in CT26-tumor-bearing mice. The “2 + 1” technetium-tricarbonyl approach leads to in vitro stable tracers, and this mixed-ligand system shows promise for further evaluation. Full article

Camptothecin (CPT) is a natural alkaloid with potent antiproliferative activity, mediated by the inhibition of Topoisomerase I (Topo I), an essential enzyme for deoxyribonucleic acid (DNA) replication. However, its clinical application has been limited by low solubility and the instability of the lactone ring under physiological conditions, both of which decrease its efficacy. Semi-synthetic analogs such as irinotecan (CPT-11) and topotecan (TPT) have been developed and approved for the treatment of various types of cancer; however, challenges related to drug resistance and side effects continue to arise. Therefore, nanomedicine and nanoparticle-based delivery systems, including nanoemulsions, liposomes, and antibody–drug conjugates (ADCs), emerge as promising strategies to improve the stability, bioavailability, and effectiveness of CPT, despite significant challenges such as scalability, pharmacokinetic variability, and regulatory requirements. This review discusses recent advances in CPT, its analogs, and these delivery platforms, highlighting its potential to optimize cancer therapy and reduce toxicity while outlining translational challenges such as scalability, pharmacokinetic variability, and regulatory requirements. Full article

Breast and prostate cancers, two of the most prevalent malignancies worldwide, pose significant therapeutic challenges owing to their resistance to conventional treatments and complex tumor microenvironments. The integration of innovative therapies into current clinical frameworks is essential for improving patient outcomes. SN-38, an active metabolite of irinotecan, exerts potent antitumor effects by inhibiting topoisomerase I and modulating the tumor microenvironment. In addition to direct cytotoxicity, SN-38 induces immunogenic cell death, promotes damage-associated molecular pattern (DAMP) release, and enhances antitumor immune responses. These dual mechanisms support the potential of combining it with chemotherapy, targeted therapy, and immunotherapy, particularly in breast and prostate cancers. However, challenges such as poor solubility, rapid degradation, and dose-limiting toxicity hinder its clinical translation. Novel delivery systems, including liposomal formulations, antibody–drug conjugates, and nanoparticle-based strategies, are being developed to address these limitations. This review summarizes the current evidence on SN-38 alone and in combination with emerging therapies, highlighting its potential as a dual cytotoxic and immune-modulating agent in resistant and aggressive cancers. Full article

Background/Objectives: Cancer is one of the world’s leading causes of death. In 2022 alone, 9.74 million people died of cancer. It is estimated that this figure will rise to 10.4 million by 2025. Prostate and breast cancer are the most frequently diagnosed cancers in the world. Methods: Notably, compound 9f displayed the highest activity against both prostate cancer (PC-3) and breast cancer (MCF-7) cell lines. It was seen that substitution on the coumarin ring had a positive effect on anticancer activity (except chlorine substitution at the 6th position of coumarin), while it had a negative effect on the selectivity index (the ratio of IC₅₀ calculated for healthy and cancer cells). Conclusions: The findings are consistent with the results obtained in the Molecular Docking study. Molecular docking studies were performed to investigate the binding affinities of the synthesized compounds towards kinesin-associated motor protein EG5, Human Ribonucleotide Reductase and Human Topoisomerase II, confirming their potent in vitro cytotoxicity against cancer cell lines. In accordance with the findings of experimental studies, compound 9f demonstrated the optimal docking binding scores. Full article

The rising resistance of bacterial and fungal strains, particularly in biofilm form, is diminishing the efficacy of available therapies and poses a major threat to human health. This highlights the need for new antimicrobial agents. A review of biological studies has shown that 2,7-naphthyridine derivatives exhibit a wide spectrum of pharmacological properties, including antimicrobial activity, which has contributed to the development of new compounds containing this scaffold. In this work, the obtained compounds were tested to assess their ability to eradicate biofilm formed by selected reference strains of opportunistic pathogens: Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans as well as towards normal microbiota representative, referred to as the Lactobacillus crispatus. The tested 2,7-naphthyridine derivatives showed selective antimicrobial activity, exclusively against S. aureus. 10j demonstrated the highest, among tested compounds, activity on this pathogen (MIC = 8 mg/L), while compound 10f exhibited ~100-fold stronger activity (MIC = 31 mg/L) than the majority of the library compounds. The in vitro assessment on fibroblast cell lines demonstrated low cytotoxicity of both compounds 10f and 10j, which was subsequently confirmed in vivo using the Galleria mellonella larval model, where no signs of systemic toxicity were observed during the 5-day observation period. Due to the structural similarity of the compounds 10f and 10j to typical gyrase/topoisomerase IV inhibitors, molecular dynamics simulations were performed on a ternary complex containing protein, DNAds, and a 1,5-naphthyridine inhibitor (PDB ID: 6Z1A). Molecular dynamics of the gyrase–DNA ternary complex supported stable binding of both hydrazone derivatives, with 10j showing slightly more favorable MM/GBSA energetics driven by electrostatics and halogen bonding, consistent with its ~4-fold lower MIC versus 10f. Taken together, our data highlight compound 10j as a promising microbiota-sparing antibacterial candidate, particularly suitable for selective interventions against S. aureus, for instance in vaginal infections, where targeted eradication of the pathogen without disturbing protective commensals is highly desirable. Full article

Background: This study investigated the therapeutic effects and underlying mechanisms of abietic acid, an abietane diterpene extracted from Pimenta racemosa var. grissea, against lung cancer. Methods: Initially, cell viability, colony formation, flow cytometry, and mitochondrial membrane potential detection were conducted to determine the impact of abietic acid on lung cancer cells. Subsequently, the antitumor mechanisms of abietic acid were predicted using network pharmacology and validated via immunofluorescence, reactive oxygen species (ROS) detection, molecular docking, gene knockdown techniques and Western blotting. Finally, an in vivo xenograft model assessed its tumor-suppressive potential, with Hematoxylin–Eosin (H&E) staining, Western blotting, and immunohistochemistry performed to examine pathological changes and protein expression alterations. Results: The proliferation of lung cancer cells was significantly inhibited by abietic acid. Additionally, abietic acid induced apoptosis and reduced mitochondrial membrane potential. Network pharmacology and Gene Ontology (GO) enrichment analysis revealed that the DNA damage response was a key biological process affected by abietic acid. Further results demonstrated that abietic acid induces DNA damage in lung cancer cells through targeting DNA topoisomerase II alpha (TOP2A). In vivo studies confirmed the antitumor efficacy of abietic acid and its low systemic toxicity. Conclusions: Abietic acid demonstrated significant antitumor effects in lung cancer cells by downregulating TOP2A, which induced DNA damage and apoptosis, revealing its clinical potential. Full article

Coumarin derivatives constitute a versatile small-molecule chemotype with broad anticancer potential. This narrative review synthesizes recent in vitro and in vivo evidence on coumarin-based scaffolds, emphasizing breast cancer and covering lung, prostate, and colorectal models. We summarize major mechanisms of action—including induction of apoptosis (caspase activation and BAX/BCL-2 balance), modulation of PI3K/Akt/mTOR signaling, inhibition of angiogenesis (VEGFR-2), interference with estrogen biosynthesis (aromatase/ER axis), chaperone targeting (Hsp90), and attenuation of multidrug resistance (efflux pumps/autophagy)—and highlight representative chemotypes (e.g., benzimidazole, triazole, furocoumarins, topoisomerase- and CDK-oriented hybrids). Where available, we contrast potency and selectivity across models (e.g., MCF-7 vs. MDA-MB-231; A549; PC-3; colon lines) and discuss structure–activity trends linking substituent patterns (heteroaryl linkers, judicious halogenation, polar handles) to pathway engagement. We also delineate translational gaps limiting clinical progress—selectivity versus non-malignant cells, incomplete pharmacokinetic and safety characterization, and limited validation beyond xenografts. Finally, we outline priorities for preclinical optimization: biology-aligned target selection with biomarkers, resistance-aware combinations (e.g., PI3K/mTOR ± autophagy modulation; MDR mitigation), and early integration of ADME/tox and PK/PD to confirm on-target exposure. Collectively, the evidence supports coumarins as adaptable, multi-target anticancer leads, particularly promising in hormone-dependent breast cancer while remaining relevant to other tumor types. Full article

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an important DNA repair enzyme and its functioning is considered as one of the possible reasons for tumor resistance to topoisomerase 1 (TOP1) poisons such as topotecan. Thus, TDP1 inhibitors in combination with topotecan may improve the effectiveness of anticancer therapy. TDP1 acts somehow in a phospholipase manner, depleting the phosphodiester bond between lipophilic tyrosine residue and 3′ end of DNA; therefore, lipophilic molecules bearing aromatic substituents can interact with TDP1 and even possess high inhibitory activity, which is evidenced by data from the literature. Previously, we identified lipophilic nucleoside derivative (compound 6d, IC₅₀ = 0.82 µM) as an effective inhibitor of the purified enzyme TDP1 that enhances the cytotoxic, DNA-damaging, and antitumor effects of topotecan. However, the role of TDP1 inhibition in this synergistic effect remained not fully understood. In the present study, we have tested the hypothesis of a TDP1-dependent mechanism of action for compound 6d, showing that it sensitizes wild-type A549 lung cancer cells, but not TDP1 knockout cells, to the cytotoxic effects of topotecan. The sensitizing effect was absent in non-cancerous HEK293A cells regardless of TDP1 status. Additionally, we analyzed the effect of compound 6d and topotecan on the expression level of TOP1 and TDP1 to determine whether the observed synergy was due to direct TDP1 inhibition and/or changes in regulation of these enzymes. The data obtained shows that compound 6d did not affect TDP1 gene expression level in HEK293A and A549 WT cells. Thus, compound 6d most probably does not suppress the transcription or mRNA stability of TDP1, and the synergistic action of 6d with topotecan is related to TDP1 inhibtion. Full article

Extracellular vesicles (EVs) secreted by glioblastoma multiforme and other types of cancer cells are key factors contributing to the aggressiveness of the disease and its resistance to therapy. Chloroquine (CHQ), a lysosomal inhibitor, has shown potential as an enhancer of temozolomide (TMZ) cytotoxicity against glioblastoma cells. Since both CHQ and TMZ are known to modulate EV secretion, we sought to investigate their potential interplay in this process. Simultaneous treatment of TMZ-sensitive (U87-MG) and TMZ-resistant (U138-MG) glioblastoma cells with TMZ and CHQ led to a synergistic upregulation of EV secretion. Although CHQ did not enhance the TMZ cytotoxicity in U87-MG cells, it synergized with the latter to upregulate the release of extracellular nucleic acids implicating activation of unconventional secretory pathways. Synergistic upregulation of the autophagy markers LC3B-II and p62 by CHQ and TMZ in both cells and EVs indicates that secretory autophagy is likely involved in the observed unconventional secretion. Moreover, a significant enrichment of caveolin-1 in small EVs highlights their potential role in modulating tumor aggressiveness. The synergy in EV upregulation was not confined to the specific biological activity of TMZ and CHQ; similar effects were observed upon co-treatments with CHQ and etoposide (a topoisomerase inhibitor) and TMZ and Bafilomycin A1 (another lysosomal inhibitor). Heightened EV release was also observed in THP-1 monocytes and macrophages treated with Bafilomycin and TMZ, highlighting a broader, cell-type-independent mechanism. These findings indicate that combined DNA damage and lysosomal inhibition synergistically stimulate secretory autophagy and EV release, potentially impacting the tumor microenvironment and driving disease progression. Full article

Background/Objectives: Intrinsically disordered protein regions (IDRs) are difficult to study due to their flexible nature and transient interactions. Computational folding using AlphaFold may offer one way to explore potential folding of these regions under various conditions. Human DNA topoisomerase IIα (TOP2A) is an essential enzyme involved in regulating DNA topology during replication and cell division. TOP2A has an IDR at the C-terminal domain (CTD) that has been shown to be important for regulating TOP2A function, but little is known about potential conformations that it may undertake. Methods: Utilizing the AlphaFold 3 (AF3) model by way of AlphaFold Server, TOP2A was folded as a dimer first without and then with 29 literature-supported post-translational modifications (PTMs) and DNA to observe whether there is predicted folding. Results: TOP2A CTD does not fold in the absence of PTMs. With the addition of PTMs, however, the CTD is predicted to fold into a globular bundle of loops and α-helices. While DNA alone did not induce folding, in the presence of PTMs, DNA ligands increased helicity of the folded CTD and caused it to interact at different core domain interfaces. In addition, DNA is predicted to enable folding of the TOP2A CTD in the presence of fewer PTMs when compared to the absence of DNA. Conclusions: AF3 predicts the folding of TOP2A CTD in the presence of specific PTMs, and this folding appears to shift to allow binding to DNA in functionally relevant regions. These studies provide predicted folding patterns that can be tested by biochemical approaches. AF3 may support the development of testable hypotheses regarding IDRs and enables researchers to model protein-DNA interactions. Full article

Promising protein targets are observed to play a role in multiple pathways across a variety of diseases, such as the regulation of immune responses, cell cycle, senescence, and DNA repair. The oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) can coordinate all these cell characteristics predominately by inhibiting the activity of the serine threonine protein phosphatase 2A (PP2A). CIP2A directly interacts with PP2A and other proteins, such as the DNA damage protein topoisomerase II-binding protein 1, to regulate signal transduction. CIP2A is overexpressed in many human cancers, including small and non-small cell lung cancers. High CIP2A expression in lung cancer correlates with poor prognosis, increased tumor proliferation, and resistance to targeted therapies or chemotherapy. Interestingly, CIP2A expression or signaling is also observed in several non-cancerous pulmonary diseases, such as chronic obstructive pulmonary disease. CIP2A can determine whether DNA-damaged cells enter mitosis and can mediate whether DNA repair occurs. CIP2A is also a regulator of inflammation and possibly fibrotic responses. Its functions are linked to altered NFκB activation and TNFα, IL-1β, IL-4, IL-6, IL-10, IL-13, and TGFβ signaling. This review outlines the possible impact of CIP2A-mediated signaling in pulmonary diseases, the processes that regulate CIP2A responses, CIP2A-dependent pathways, and potential therapeutic strategies targeting CIP2A. Substantial medicinal chemistry efforts are underway to develop therapeutics aimed at modulating CIP2A activity. The development of specific inhibitors of CIP2A that selectively target its expression or protein stability could improve our understanding of CIP2A’s function in pulmonary diseases. Full article

Cardiotoxicity is one of the most important adverse events of chemotherapy regimens, especially of anthracyclines. Different mechanisms are associated with chemotherapy-related cardiac dysfunction (CTRCD): oxidative stress, mitochondrial dysfunction, inhibition of topoisomerase 2 beta, abnormal iron metabolism, apoptosis, and fibrosis. Even after years of investigation, the early detection and prevention of cardiac impairment after chemotherapy through biomarkers remains an unmet need. The differential expression of microRNAs (miRs) in plasma at different timepoints (baseline, stable intervals during and at the end of chemotherapy) has been associated with CTRCD. Namely, some miRs, such as let-7, miR-29 and miR-30 family, miR-1 clusters, miR-34a, miR-126, miR-130a, miR-140, miR-320a, and miR-499, could play prognostic and/or diagnostic roles in CTRCD. Key miRs involved in apoptosis and oxidative stress include miR-1, miR-21, miR-30 and miR-130a, while let-7 family, miR-34a, miR-29b and miR-499 are associated with fibrosis and extracellular matrix remodeling. Additionally, mitochondrial function is regulated by miR-30, miR-130a and miR-499. Expanding its role, miR-130a could act as a therapeutic agent of CTRCD through its inhibition. This narrative review focuses on the current understanding of miRs’ involvement in CTRCD pathophysiology, summarizes the evidence linking miRs with cardiotoxicity risk, and explores the potential of miRs as biomarkers and therapeutic targets to improve early detection, risk stratification, and management of CTRCD. Full article

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a key enzyme for the repair of stalled topoisomerase 1 (TOP1)-DNA complexes. Previously, we obtained HEK293A cells with homozygous knockout of the TDP1 gene by the CRISPR/Cas9 method and used them as a cell model to study the mechanisms of anticancer therapy and to investigate the effect of TDP1 gene knockout on gene expression changes in the human HEK293A cell line by transcriptome analysis. In this study, we investigated the effect of a TDP1 inhibitor ((R,E)-2-acetyl-6-(2-(2-(4-bromobenzyliden) hydrazinyl) thiazol-4-yl)-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d] furan-1(9bH)-one, OL9-119, an usnic acid derivative), capable of potentiating the antitumor effect of topotecan, as well as its combination with topotecan, on the transcriptome of wild-type and TDP1 knockout HEK293A cells. OL9-119 was found to be able to reduce cell motility by decreasing the expression of a number of genes, which may explain the antimetastatic effect of this compound. Differentially expressed genes (DEGs) related to electron transport, mitochondrial function, and protein folding were also identified under TDP1 inhibitor treatment. Full article