Search Results (389)

Benzoxaboroles have garnered significant interest for their therapeutic potential in various diseases. Among them, 7-propanamide benzoxaborole has served as a new and valuable chemotype for anti-cancer agents, although their definitive intracellular target(s) remains elusive. Herein, three-dimensional quantitative structure–activity relationship (3D-QSAR) was used to systematically investigate the structure–activity relationships (SAR) of a series of 7-propanamide benzoxaboroles. Comparative molecular field analysis (CoMFA, r² = 0.991, q² = 0.626) and comparative molecular similarity indices analysis (CoMSIA, r² = 0.964, q² = 0.605) revealed critical structural determinants of 7-propanamide benzoxaboroles for inhibition of the ovarian cancer cell (SKOV3) proliferation. Based on the guidance of the critical structural determinants, we designed a new benzoxaborole compound 42 with high predicted inhibition activity values. In vitro proliferation assessment showed that compound 42 exhibited superior inhibitory potency to lead compound 1 and comparable activity to compound 41. These findings indicated that the SAR of benzoxaborole compounds through 3D-QSAR can offer valuable theoretical insights for the structural optimization of new benzoxaboroles as anti-SKOV3 agents. Full article

Mitochondrial oxidative phosphorylation serves as a critical driving force in the progression of ovarian cancer. Recent studies have demonstrated that copper induces mitochondrial-dependent programmed cell death by directly binding to the thioacylated components of the tricarboxylic acid (TCA) cycle. The involvement of copper in OXPHOS complex IV, a rate-limiting step in the mitochondrial respiratory chain, suggests that the role of mitochondria in mediating copper-induced cell death can be further elucidated through the study of OXPHOS complex IV. The findings of this study indicate that the cuproptosis process in ovarian cancer, induced by Elesclomol, is associated with mitochondrial complex IV, with LRPPRC identified as a crucial factor. Following Elesclomol treatment of ovarian cancer cells, there was a notable increase in mitochondrial reactive oxygen species (ROS), a significant accumulation of the copper death marker protein DLAT, and a marked decrease in the lipoic acid synthesis-related protein FDX1. Furthermore, the expression levels of copper ion transporters ATP7B and CTR1, which are involved in the assembly and translation of complex IV, as well as the core subunit MTCO1 of complex IV, the copper chaperone protein SCO1, and the interacting protein LRPPRC, were significantly diminished. Inhibition of the IV-stabilizing protein LRPPRC in the ovarian cancer cell lines A2780 and SKOV3 through RNA interference resulted in increased sensitivity to Elesclomol. Concurrently, the expression levels of FDX1, LIAS, LIPT1, SCO1, and MTCO1 decreased significantly. These findings suggest that LRPPRC plays a role in inhibiting the expression of lipoic acid and copper chaperone proteins during Elesclomol-induced copper death in ovarian cancer. This inhibition collectively diminishes the expression and activity changes in complex IV, induces mitochondrial dysfunction, and promotes cuproptosis in ovarian cancer. This study further demonstrates that inhibiting the oxidative phosphorylation complex IV can enhance copper-induced cell death in ovarian cancer. Full article

Background: Marine-derived secondary metabolites such as phlorotannins from the edible brown alga Ecklonia cava exhibit diverse bioactivities. However, their mechanisms in inflammation-associated cancer remain insufficiently understood. Methods: This study explored the anticancer potential of three major phlorotannins (dieckol, 7-phloroeckol, and 8,8′-bieckol) through network pharmacology, molecular docking, molecular dynamics simulations, and in vitro validation in SKOV3 ovarian cancer cells and tumor-associated macrophages (TAMs). Results: Computational analyses revealed stable binding of phlorotannins to IL-17RA, with 7-phloroeckol and 8,8′-bieckol preferentially engaging loop-proximal regions of the receptor, while dieckol interacted with spatially distinct residues. In SKOV3 ovarian cancer cells, phlorotannins suppressed migration and invasion by approximately 40 to 60%, accompanied by reduced MMP expression linked to IL-17RA–Act1 signaling attenuation and by increased TIMP1 expression in association with transient ERK1/2 activation. In TAMs, phlorotannins attenuated pro-tumorigenic cytokine production and polarization marker expression, indicating suppression of tumor-supportive immune activity. Conclusions: Collectively, these findings demonstrate that E. cava-derived phlorotannins exert anti-metastatic effects through dual regulation of IL-17RA/Act1 and ERK1/2 signaling pathways, offering mechanistic insight into their therapeutic potential against inflammation-driven malignancies. Full article

Radionuclide-based molecular imaging modalities are active and developing areas of functional and molecular diagnosis. Among the radionuclides used for SPECT imaging in oncology, ^99mTc is a leading candidate for radiolabeling. At present, a sufficient number of complexons for ^99mTc have been described; however, the development of effective delivery systems for this isotope to the area of interest is a complex research task. The use of tumor-targeting molecules as carriers for radioactive tracers is an effective strategy that has enabled the development of many novel radiopharmaceuticals for cancer imaging. Background: To date, a number of studies have shown tumorotropicity of tetrapyrrole compounds to tumor tissues, in particular derivatives of natural chlorophyll A. Methods: Purification was performed using solid-phase extraction. Assessment of radiochemical yield and purity was performed via radio-ITLC. The in vitro tumor cell accumulation was assessed using SKOV-3 and A-431 cell lines. Dose-dependent biodistribution was evaluated in Nu/J mice bearing epidermoid carcinoma (A-431) xenografts. Results: In this work, we obtained complexes with ^99mTc based on water-soluble carboxylate chlorin e₆ derivatives in order to evaluate their potential for use as SPECT radiopharmaceuticals. We performed radiolabelling optimization of a series of the novel chlorins and primary preclinical studies, including an assessment of the effect of their lipophilicity and charge on tumor uptake. Conclusions: Modification of the periphery of the chlorin macrocycle with chelating groups allows for complexing a wide range of metals, including ^99mTc, which can be used for targeted delivery of the radionuclide to the area of interest. Full article

This study aimed to evaluate the antiproliferative, apoptotic, and oxidative stress-inducing effects of the combination of metformin and doxorubicin (adriamycin) in OVCAR3 and SKOV3 ovarian cancer cell lines and to investigate the potential synergistic interactions between the two agents. Cell viability was assessed using the MTT assay. Apoptosis was quantified via Annexin V/PI staining followed by flow cytometry. Caspase-8 and caspase-9 activities were measured using colorimetric assays. Oxidative stress parameters, including reactive oxygen species (ROS) and nitric oxide (NO), were determined using DCFH-DA fluorescence and the Griess assay, respectively. The mRNA expression levels of apoptosis-related genes (Bcl-2, Survivin, Bax, and Caspase-3) were analyzed by qRT-PCR. Drug interaction and synergy were evaluated using the Chou–Talalay combination index (CI) model and the highest single agent (HSA) model. Prognostic relevance of target genes and protein interaction networks was examined through TCGA and STRING databases. The metformin–doxorubicin combination demonstrated strong synergistic antiproliferative effects in both cell lines (CI < 0.7 in OVCAR3). The combination significantly increased apoptosis compared with single-agent treatments, yielding a total apoptotic rate of 62.5 ± 4.2% in OVCAR3. Caspase-8 and caspase-9 activities were elevated by 5.6 ± 0.7-fold and 7.3 ± 0.8-fold, respectively. Combination treatment also induced marked oxidative stress, increasing NO levels to 12.4 ± 1.1 µM and ROS levels to 412 ± 25% in OVCAR3 cells. qRT-PCR analyses revealed downregulation of anti-apoptotic Bcl-2 (0.28 ± 0.04-fold) and Survivin (0.25 ± 0.03-fold), along with upregulation of pro-apoptotic Bax (5.8 ± 0.6-fold) and Caspase-3 (6.5 ± 0.7-fold). Bioinformatic analyses indicated that high Bcl-2 and Survivin expression correlated with poorer overall survival in ovarian cancer patients. Metformin enhances the anticancer efficacy of doxorubicin through synergistic activation of intrinsic and extrinsic apoptotic pathways, induction of oxidative and nitrosative stress, and transcriptional regulation of key apoptotic markers. These findings support the potential use of metformin as an adjuvant agent to strengthen doxorubicin-based chemotherapy in ovarian cancer. Full article

Background/Objectives: Ovarian cancer remains one of the most lethal gynecologic malignancies, primarily due to late diagnosis and the development of chemoresistance. Adriamycin (ADR) is effective but limited by systemic toxicity. Natural bioflavonoids such as hesperidin (Hes) may enhance chemotherapy efficacy through oxidative, apoptotic, and immune modulation. This study investigated the antiproliferative, pro-apoptotic, and immunomodulatory effects of Hes and ADR in human ovarian adenocarcinoma cells (SKOV3), focusing on Forkhead box P3 (FOXP3) and epidermal growth factor receptor (EGFR) signaling pathways. Methods: SKOV3 were treated with increasing concentrations of Hes (10–400 µM) and ADR (0.01–0.4 µM), either individually or in combination at their half-maximal inhibitory concentration (IC₅₀) ratios. Cell viability (MTT assay), gene expression (qRT-PCR), cytokine levels (ELISA), and total antioxidant capacity (TAC) were assessed to evaluate treatment responses. Results: Both agents reduced cell viability in a dose- and time-dependent manner, with the combination exhibiting synergistic cytotoxicity after 48 h. Co-treatment markedly upregulated Caspase-3 and Bax while downregulating FOXP3 and EGFR. Antioxidant capacity was significantly enhanced in the Hes-treated and combination groups (p < 0.001). Conclusions: Hes and ADR synergistically suppressed proliferation, induced apoptosis, and modulated cytokine balance by inhibiting FOXP3- and EGFR-mediated oncogenic signaling. This combination demonstrates strong potential as an adjuvant therapeutic strategy for ovarian cancer. Full article

Background and Objectives: Currently, the development of local drug delivery systems for the treatment of cancer patients is a pressing issue. Such systems allow for the targeted delivery of anticancer drugs directly to the tumor site, ensuring prolonged drug release or reducing the risk of recurrence after tumor removal, minimizing the impact on healthy tissues and thereby reducing the overall toxic load on the body. This work is devoted to evaluating the prospects of using scaffolds based on low-modulus titanium Ti-15Mo alloy with a biomimetic coating as a platform for the local administration of the cytostatic drug cisplatin into the patient’s body. Methods: Porous coatings were obtained by plasma electrolytic oxidation in an aqueous solution of sodium phosphate and calcium acetate with the addition of various components. The influence of coating parameters on the corrosion resistance of samples and on the antiproliferative effect of cisplatin-loaded scaffolds was evaluated. Human K562 hemoblastosis, HT116 intestinal cancer, and SKOV3 ovarian cancer cell lines were used as cell models. Results: It was shown that the addition of sodium phosphate (the PS type electrolyte) provides the formation of a coating with a developed system of interconnected pores characterized by an attractive combination of parameters: high porosity (17%), high pore size (3.9 μm), and considerable thickness (17.4 μm). This coating demonstrated the best corrosion resistance in a Ringer solution as compared to the other tested states. In addition, the PS coating loaded with cisplatin exhibited a pronounced cytotoxic effect on cancer cells. This effect was attributed to its ability to fix cisplatin on the surface, which slows down its release into the extracellular environment, increasing the time of its action, thereby contributing to a more effective (by more than 3 times) suppression of tumor cell proliferation compared to the action of the standard form of the drug in the form of a solution when changing the growth medium and subsequent incubation for 48 h. Conclusions: PS scaffolds made of low-modulus titanium alloy Ti-15Mo with a biomimetic surface in an electrolyte based on an aqueous solution of sodium phosphate and calcium acetate with the addition of sodium silicate can be used as an advanced platform for the local delivery of the cytostatic drug cisplatin, which makes them promising for application in orthopedic oncology. Full article

Ovarian cancer (OC) is usually diagnosed at an advanced stage, contributing to its high mortality rate. The presence of concurrent bacterial infections in these patients is a common clinical observation, and the mechanisms by which this coinfection influences tumor progression are still not fully understood. This study investigates the role of polydisperse extracellular vesicles (PEVs) secreted by OC cells in response to bacterial components, aiming to elucidate a potential communication pathway between OC and the bacterial microenvironment. We stimulated a human OC cell line in vitro with a fraction of E. coli. Our results show that this bacterial stimulation significantly increases the secretion of PEVs by cancer cells. A subsequent proteomic analysis of these PEVs revealed an enrichment of proteins, including filamin A, filamin B, alpha-enolase, and heat shock cognate 71 kDa protein. In addition, the PEVs displayed protease activity (on fibronectin and gelatin) and phosphatase activity against para-nitrophenyl phosphate, indicating their capacity to alter cellular signaling. This represents a novel mechanism through which bacterial coinfection may influence the biological behavior of OC if bacteria interact with tumor cells, potentially contributing to their aggressiveness and the challenges associated with their treatment. Our work highlights the importance of studying the interplay between the tumor and its associated microbiota to better understand ovarian cancer progression and identify new therapeutic targets. Full article

Background: Physical plasma, the fourth state of matter formed through gas ionization, has shown promise in various clinical applications, including wound healing and antimicrobial therapy. Recently, Non-invasive physical plasma (NIPP) selectively disrupts tumor cell proliferation and metabolism without inducing cytoprotective stress responses, positioning it as a promising adjunct in oncological therapies, though its underlying mechanisms remain insufficiently understood. Methods: In this study, we investigated the effects of NIPP (Plasma Care device) on six tumor cell lines, ovarian (SKOV-3, OVCAR-3), prostate (LNCaP, PC-3), and breast (MCF-7, MDA-MB-231). Cell proliferation and migration were assessed using CASY analysis and scratch assays, while cytoskeletal integrity, heat shock protein (HSP) expression, and key metabolic indicators were evaluated through immunofluorescence, Western blotting, and biochemical assays. Results: NIPP treatment significantly inhibited tumor cell proliferation and migration, disrupted cytoskeletal organization, and altered metabolic activity in a time-dependent manner. These effects were associated with increased intracellular reactive oxygen species (ROS), decreased mitochondrial membrane potential (MMP), enhanced glycolysis, and elevated lactate production. Notably, despite cellular stress, neither HSP expression nor superoxide dismutase (SOD) activity showed significant changes, suggesting a lack of classical stress-response activation. Conclusions: Our findings indicate that NIPP selectively impairs tumor cell function by inducing oxidative stress and metabolic disruption, without triggering protective HSP-mediated resistance pathways commonly seen in radiotherapy and chemotherapy. These results highlight the therapeutic potential of NIPP, particularly via the Plasma Care device, as a novel anticancer strategy. Full article

N-vinylindoles have attracted attention for their promising role in medicinal chemistry. Therefore, developing new synthetic methods that enable access to diverse functionalized N-vinylindoles with potential pharmacological properties is highly valuable. 1-[2-aryl-1-(4,5-dihydro-1H-imidazol-2-yl)vinyl]-1H-indoles 2a-i were prepared via Knoevenagel condensation promoted by 1H-benzotriazole, and characterized by IR, NMR, and MS spectroscopic data as well as a single-crystal X-ray diffraction-based study of the representative derivative 2g. The obtained compounds 2a-i were screened for their cytotoxic potency against human cancer cell lines (HeLa, SKOV-3, AGS) and non-cancerous cell line (HaCaT) using the MTT assay. Additional apoptosis analysis and cell cycle assay on SKOV-3 cells were conducted. Their antimicrobial activity was determined using reference strains of S. aureus, E. coli, C. albicans, and C. glabrata. The potent inhibitory activity against AGE2-BSA/sRAGE interaction of selected N-vinylindoles 2b, 2d-f, and 2h-i was evaluated by ELISA assay. A facile approach has been developed for the synthesis of a novel class of N-vinylindoles. The preliminary structure–activity considerations indicated that the presence of substituents R, such as 4-bromophenyl (compound 2f) or 2-naphthyl (compound 2i) is optimal for anticancer activity and the AGE2-BSA/sRAGE interaction inhibition. The most prominent (Z)-1-[1-(4,5-dihydro-1H-imidazol-2-yl)-2-(naphthalen-2-yl)vinyl]-1H-indole (2i) was found to strongly arrest cell cycle in the SKOV-3 cell line in the subG0 phase, inducing apoptosis. Notably, derivative 2i also exhibited the highest activity against S. aureus and C. albicans strains within the tested series. These findings highlight the substantial potential of N-vinylindole derivative 2i as a lead compound for the development of anticancer drugs with additional inhibitory activity on the AGE/RAGE interaction. Full article

Background/Objectives: This study evaluated the antifungal, enzyme inhibitory, and anticancer properties of the ethyl acetate (EtOAc) leaves extract of Rubus ulmifolius Schott using in vitro assays and in silico analysis. Methods: Antifungal activity was assessed against five fungal strains by measuring inhibition zones. Enzyme inhibition assays were conducted for acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and urease. Antiproliferative effects were tested against HT-29 colorectal, SK-OV-3 ovarian, and A549 lung cancer cells using the MTT assay. Network pharmacology and molecular docking analyses were performed on major compounds previously identified by GC–MS (gallic acid, caffeic acid, catechin, and fructofuranose) to uncover the potential mechanisms of the plant in colorectal and ovarian cancers. Results: The extract displayed notable antifungal activity, particularly against Penicillium sp., Aspergillus fumigatus, and Candida albicans, with inhibition zones of 22.5 ± 0.7 to 26.8 ± 1.3 mm. Enzyme assays revealed moderate inhibition of AChE (IC₅₀ = 92.94 ± 1.97 µg/mL), weaker activity against BChE (IC₅₀ = 274.93 ± 2.32 µg/mL), and modest inhibition of urease (IC₅₀ = 262.60 ± 1.41 µg/mL). The extract exhibited strong antiproliferative effects against HT-29 and SK-OV-3 cells (IC₅₀ = 2.41 ± 0.13 and 4.63 ± 0.26 µg/mL, respectively), whereas activity against A549 lung cancer cells was limited. Network pharmacology predicted 52 and 44 overlapping target genes between the major compounds and colorectal and ovarian cancers, respectively. Protein–protein interaction networks identified hub genes for each cancer type, with key shared targets including EGFR, ESR1, PTGS2, and STAT3. Molecular docking confirmed favorable binding between these targets and the compounds, particularly catechin, which showed interactions comparable to those of reference inhibitors. Conclusions: These findings suggest that R. ulmifolius may possess multi-target antifungal, neuroprotective, and anticancer potential, warranting further in vitro pharmacological and preclinical validation. Full article

Background/Objectives: In the fight against ovarian cancer, various therapies have been employed, with a strong focus on developing novel derivatives of existing substances. Methods: In this study, we continue our research on novel xanthone derivatives in combination with mild hyperthermia, targeting ovarian cancer cell lines TOV-21G and SK-OV-3. Using qPCR arrays, we analyzed 84 cellular stress-related genes categorized into anti-oxidant and pro-oxidant enzymes, molecular chaperones, and xenobiotic metabolism including the cytochrome P450 group. Furthermore, we conducted in silico analyses to investigate the pathways of the most affected genes, gene set enrichment, and gene ontology. Results: The most significant changes were observed in SOD2, SOD3, CYP2F1, CYP1B1, and HMOX1. Additional changes related to drug toxicity and the postulated mechanism of action were also identified. Based on in silico analyses, we concluded that the primary node of hyperthermia-induced changes is HSPA1A. Heat-induced alterations predominantly revolve around misfolded proteins, monooxygenase activity, and ATPase activity. Conclusions: To summarize, the combined therapy of novel xanthone derivatives and mild hyperthermia shows promising results and warrants further investigation to fully elucidate the mechanisms of action underlying these effects. Full article

Twelve undescribed peptidic compounds, bukhansantaibols A–K (1–10) and bukhansantaibals A–B (11–12), were isolated from the soil fungus Trichoderma atroviride through LC-MS and bioactivity-guided purification. Their structures were elucidated by the analysis of 1D and 2D NMR spectra, HRESIMS, and acid hydrolysis using modified Marfey’s method. All compounds were evaluated for their cytotoxic activity against HCT-8 (colon cancer) and SK-OV-3 (ovarian cancer) cells. Among them, compounds 1–5 exhibited significant inhibitory effects, with IC₅₀ values ranging from 2.1 to 19.6 μM. Full article

Background/Objectives: Ovarian cancer (OC) remains one of the most lethal malignancies of the female reproductive system. Glucose oxidase (GOx) has emerged as a potential therapeutic agent in cancer treatment by inducing tumor starvation through glucose depletion. Nonetheless, its clinical application is constrained due to its systemic toxicity, immunogenicity, poor in vivo stability, and short half-life. These challenges can be addressed through nanotechnology; in particular, biogenic mesoporous silica nanoparticles (MSNs) offer promise as drug delivery systems (DDSs) that enhance therapeutic efficacy while minimizing side effects. Methods: Biogenic MSNs were extracted from the Equisetum myriochaetum plant via acid digestion, functionalized with 3-aminopropiltrietoxysilane (APTES) and glutaraldehyde (GTA), and loaded with GOx. The free and immobilized MSNs were characterized using FTIR, DLS, XRD, SEM/EDX, and BET techniques. A colorimetric approach was employed to quantify the enzymatic activity of both the free and immobilized GOx. The MTT assay was employed to assess the viability of SKOV3 cells. The obtained IC₅₀ concentration of the nanoformulation was administered to SKOV3 cells to analyze the expression of cancer-related genes using RT-qPCR. Results: IC₅₀ values of 60.77 ng/mL and 111.6 µg/mL were ascertained for the free and immobilized GOx, respectively. Moreover, a significant downregulation of the oncogene β-catenin (CTNNB1) was detected after 24 h with the nanoformulation. Conclusions: Our findings indicate that GOx-loaded biogenic MSNs may serve as a potential therapeutic agent for ovarian cancer. This is, to the best of our knowledge, the first report exploring the effect of GOx-loaded biogenic MSNs on SKOV3 cells. Full article

Background/Objectives: The dual targeting of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) represents an effective approach for cancer treatment. The current study involved the design, synthesis, and biological evaluation of a new series of purine-containing hydrazones, 6–24 (a,b), as anticancer agents targeting EGFR and HER2 kinases. Methods: The proposed compounds were initially screened in silico using molecular docking to investigate their binding affinity to the active sites of EGFR and HER2 kinase domains. Subsequently, the compounds were synthesized and evaluated in vitro for their antiproliferative activity, using the MTT assay, against the various cancer cell lines A549, SKOV-3, A2780, and SKBR-3, with lapatinib as the reference drug. The most active derivatives were then examined to determine their inhibitory activity against EGFR and HER2 kinases. Results: Among the assessed compounds, significant antiproliferative activity was demonstrated by 19a, 16b, and 22b. 19a exhibited substantial anticancer efficacy against A549 and SKBR-3, with IC₅₀ values of 0.81 µM and 1.41 µM, respectively. This activity surpassed lapatinib, which has an IC₅₀ of 11.57 µM on A549 and 8.54 µM on SKBR-3 cells. Furthermore, 19a, 16b, and 22b exhibited superior EGFR inhibitory efficacy compared with lapatinib (IC₅₀ = 0.13 µM), with IC₅₀ values of 0.08, 0.06, and 0.07 µM, respectively. Regarding HER2, 22b demonstrated the greatest potency with an IC₅₀ of 0.03 µM, equipotent to lapatinib (IC₅₀ = 0.03 µM). Flow cytometry analysis of A549 cells treated with 19a and 22b indicated their ability to arrest the cell cycle during the G1 phase and to trigger cellular apoptosis. Conclusions: Compounds 19a, 16b, and 22b represent intriguing candidates for the development of an anticancer agent targeting EGFR and HER2 kinases. Full article