Search Results (377)

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

From a previously performed proteomics screen, GPP130, or Golgi phosphoprotein of 130 kDa, was identified as a potential substrate of the proprotein convertase 7 (PC7; PCSK7). GPP130 is a type-II transmembrane protein with a luminal domain containing endosomal and Golgi-retrieval determinants, enabling a unique trafficking route. Most of the previous work on GPP130 relates to its binding and retrograde trafficking of the Shiga toxin. However, its cellular biology and its biochemical characterization remain understudied. Recently, GPP130 was reported to be implicated in cell cycle progression and cell proliferation in head and neck cancer cells. This led us to analyze the cBioPortal for Cancer Genomics, revealing that the GPP130/GOLIM4 gene is amplified in many cancers, including lung, ovarian, and cervical. This observation led us to use the A549 lung cancer cell line to investigate the growth-regulating roles of endogenous and overexpressed GPP130 and to analyze the impact of its cleavage/shedding by PC7 and/or Furin on cellular growth. Our cell-based assays suggest that GPP130 is a novel pro-protein convertase substrate that increases cell proliferation in A549, SKOV3, and HeLa cells, and that the latter activity is enhanced following its cleavage by PC7 and/or Furin into a membrane-bound N-terminal product and secreted C-terminal fragments. This novel work sheds light on the cell biology of the poorly characterized GPP130, its proliferative activity, and modulation upon its shedding by PC7 and Furin in lung cancer progression. Full article

Background: Ovarian cancer is a major challenge in oncology due to high mortality rates, especially in advanced stages, despite current therapeutic approaches relying on chemotherapy and surgery. The search for novel therapeutic strategies is driven by the need for more effective treatments. This study focuses on novel xanthone derivatives modified with a morpholine ring, aiming to improve anticancer efficacy. Methods: In silico studies were conducted using ProTox III and SwissADME databases to assess the toxicity and ADME properties of the synthesized compounds. Molecular changes in cellular stress-related genes were investigated through qPCR in two ovarian cancer cell lines (TOV-21G and SKOV-3) following treatment with the compounds. Results: In silico analyses predicted high gastrointestinal absorption and blood–brain barrier permeability for the derivatives. Compounds exhibited varying toxicity and metabolic profiles. qPCR revealed significant alterations in genes related to antioxidant enzymes, molecular chaperones, and xenobiotic metabolism, indicating potential mechanisms of action and cellular responses to the compounds. Conclusions: The study demonstrates the potential of novel xanthone derivatives as promising candidates for ovarian cancer therapy, with implications for enhancing therapeutic efficacy and addressing drug resistance. Further research is warranted to elucidate the precise mechanisms underlying the observed effects and to develop tailored treatment strategies leveraging these agents. Full article

A series of novel podophyllotoxin derivatives containing benzothiazole scaffolds were synthesized and evaluated for their in vitro cytotoxic activity against five cancer cell lines (MCF-7, SKOV-3, B16F10, LOVO, and HeLa). Two compounds, 7 and 11, which are different only by the absence or presence of the ester group, showed the strongest cytotoxic effect towards all tested cancer cell lines with the IC₅₀ 0.68–2.88 µM. In addition, it was demonstrated that these compounds inhibit cancer cell proliferation by inducing G2/M phase arrest in HeLa cells. The structure–activity relationship was analyzed and it confirmed the importance of the core structural features like a dioxolane ring and free-rotating trimethoxyphenyl group for cytotoxicity. Moreover, the R configuration of the ester group at the C-8′ position proved to be substantial since its epimer was inactive. The molecular docking studies revealed that the most potent compounds have a different binding mode to β-tubulin than podophyllotoxin; however, the benzothiazole fragment docked in a similar location as the trimethoxyphenyl group of podophyllotoxin, exhibiting similar hydrophobic interactions. These findings clearly indicate that podophyllotoxin–benzothiazole derivatives could be addressed for further pharmacological studies in anticancer research. Full article

This paper presents the influence of acetylation on the cytotoxic and antioxidant activity of natural triterpenes. Oleanolic acid, betulin, betulinic acid and other triterpenes have been modified to improve their pharmacological properties. Acylation of the hydroxyl group at the C-3 position showed significant changes in biological activity, in particular against cancer cell lines such as HeLa, A-549, MCF-7, PC-3 and SKOV-3, with the highest IC₅₀ results for acetyloleanolic acid (1b) and acetylbetulinic acid (4b). Docking results showed that all compounds tested demonstrated the ability to bind to pockets (C1–C5) of the p53 Y220 protein, obtaining different Vina score values. The strongest binding was observed for compound 2b in the C3 pocket (−10.1 kcal × mol⁻¹), while in the largest C1 pocket, the best result was achieved by compound 5b (−9.1 kcal × mol⁻¹). Moreover, antioxidant studies using the CUPRAC and DPPH tests showed significant differences in the mechanisms of action of the compounds depending on the structure. The analyses of ADMETox confirmed the favorable pharmacokinetic profile and low toxicity of most of the tested derivatives. The results suggest that acetylated triterpenes, especially 1b and 4b, have great potential as anticancer drug candidates, requiring further research on their cytotoxic activity and structural modifications. Full article

Ovarian cancer (OC) is the most lethal gynecologic malignancy worldwide, with high rates of disease relapse posing a significant therapeutic challenge. Consequently, there is an urgent need to develop novel treatments for OC. This study aims to evaluate the effects of the novel imipridone, ONC206, both as a monotherapy and in combination with the standard of care chemotherapy drug, cisplatin (CDDP), on human OC cell lines. In order to study the effect of ONC206 and CDDP on ovarian cancer, two cell lines, OVCAR-420 and SKOV-3, were used in this study. Cell proliferation was assessed using MTT assay while cell viability was evaluated using the trypan blue exclusion assay. Cell migration was examined using the wound healing assay. To investigate the effects of both treatments, alone or in combination on the stem-cell-like population of OC cells, the sphere-forming assay was employed. Our results revealed that ONC206, alone or in combination with CDDP, exerts a potent anti-proliferative effect on both OVCAR-420 and SKOV-3 cells, as shown in the MTT and trypan blue exclusion assays. Interestingly, a synergistic effect was observed when ONC206 was combined with CDDP, enhancing the overall anti-cancer efficacy. Additionally, ONC206 alone or in combination with CDDP inhibited the migratory ability of the ovarian cancer cells. Furthermore, the activity of ovarian cancer stem cells was inhibited when cells were treated with ONC206 alone or in combination with CDDP, as shown in the significant decrease in both the size and the sphere-forming ability of ovarian cancer stem cells in the 3D culture model. Our results highly suggest the potential of imipridones as a new class of therapeutics in ovarian cancer management. Among these, ONC206 shows nanomolar potency, highlighting its potential as a standalone therapy or in combination with existing treatment regimens. Full article

Extracellular vesicles (EVs) play pivotal roles in tumor progression and metastasis by mediating intercellular communication within the tumor microenvironment. In this study, we identified two novel EX cargo proteins—UBE2NL and HIST2H3PS2—derived from highly aggressive epithelial ovarian cancer (EOC) cells and mesenchymal-type ovarian stromal progenitor cells (MSC-OCSPCs) but absent in less aggressive SKOV3 cells. Quantitative proteomic profiling via LC-MS/MS and TCGA-integrated analysis revealed that high expression of these genes correlated with advanced tumor stages and poor overall survival in EOC, and high HIST2H3PS2 expression predicted poor survival in endometrial cancer (EC). Functionally, UBE2NL and HIST2H3PS2 overexpression promoted EOC cell invasiveness, which was further enhanced by EX-mediated autocrine and paracrine effects. In contrast, the knockdown of UBE2NL reduced cell invasiveness and prolonged mouse survival in vivo. Moreover, HIST2H3PS2-enriched EXs significantly increased peritoneal dissemination and ascites in murine models. These findings suggest that EX-packaged UBE2NL and HIST2H3PS2 drive tumor aggressiveness and metastasis in gynecologic cancers, highlighting their potential as prognostic biomarkers and therapeutic targets. Full article

Ovarian cancer (OC) is a gynecological cancer characterized by high morbidity and mortality associated with poor survival outcomes. Bisphenol F (BPF), a widely used analog of bisphenol A (BPA), has recently gained attention due to its potential endocrine-disrupting properties and ubiquitous environmental presence. However, the carcinogenic potential of BPF in OC has not been well explored. This study investigates the effects of BPF on ovarian carcinogenesis by assessing its pathological impact on cellular processes, including cell proliferation, wound healing, and cell invasion. OC cells, SKOV3 were treated with varying concentrations of BPF (0.01–250 µM). Cell viability was assessed using Alamar Blue assay, and migration ability was analyzed using wound-healing assay. Further, the total antioxidative capability (T-AOC) was measured. Statistical analysis was performed using student’s-t-test/ANOVA, with a significance set at p < 0.05. BPF exhibited a dual role in cell viability, enhancing cell proliferation at low concentrations (1 µM: p = 0.034; 10 µM: p = 0.012) while exerting cytotoxic effects at higher concentrations (250 µM: p = 0.021). Further, a wound-healing assay demonstrated that a lower concentration, 1 µM BPF promoted cell migration (p = 0.0345), indicating its involvement in OC. However, a non-significant difference was observed in the invasive potential and T-AOC of BPF-treated SKOV3 cells. Our findings provide key insights into the effects of BPF on cellular processes linked with ovarian carcinogenesis, emphasizing the need for future experiments to comprehend its mechanisms of action. Full article

Background: Cisplatin resistance is a major cause of tumor recurrence and mortality in high-grade serous ovarian cancer (HGSOC). Extrachromosomal circular DNA (eccDNA) has emerged as a critical factor in tumor evolution and drug resistance. However, the specific contribution of eccDNA to cisplatin resistance in HGSOC remains unclear. Methods: We performed whole-genome sequencing, Circle-Seq, and RNA-Seq in four pairs of primary and cisplatin-resistant (cisR) HGSOC cell lines to characterize genome-wide eccDNA distribution and features. Functional enrichment analyses were subsequently conducted on differentially expressed eccDNA-related genes. Results: In the SKOV3 cisR cell line, we identified a large extrachromosomal circular DNA (ecDNA) carrying the HIF1A gene, which regulates DNA repair, drug efflux, and epithelial–mesenchymal transition, contributing to cisplatin resistance. Using Circle-Seq, we detected a total of 161,062 eccDNAs, most of which were less than 1000 bp and distributed across all chromosomes. Notably, the number of eccDNAs on chromosome 21 differed significantly between the primary and cisR cell lines. Additionally, eccDNAs were predominantly located in non-coding repetitive elements. Functional analysis of eccDNA-related differentially expressed genes revealed that, compared to primary cell lines, cisR cell lines were associated with mitotic spindle assembly, regulation of vascular permeability, and cell differentiation. eccDNA-related genes involved in these pathways include MISP, WIPF1, RHOD, KRT80, and PLVAP. Conclusions: Our findings suggest that eccDNAs, particularly ecDNA amplifications like HIF1A, contribute significantly to cisplatin resistance mechanisms in HGSOC. These insights highlight eccDNA as a potential target for overcoming therapeutic resistance and improving treatment outcomes in ovarian cancer. Full article

Epithelial ovarian cancer (EOC) is a gynecological tumor with high mortality. Despite aggressive treatment, survival rates for patients with advanced EOC are low, and more effective methods of diagnosis and treatment are urgently needed. Inflammation and cancer are strongly associated; however, the mechanisms that mediate this relationship are not fully understood. In this study, we found that the expression of interleukin-1β (IL-1β), a proinflammatory cytokine, increased in an ovarian cancer tissue microarray (TMA) and inhibited A2780 and SKOV3 cell viability and metastasis. Recombinant IL-1β protein and the overexpression of IL-1β decreased the proliferation and metastasis of ovarian cancer cells. IL-1β deficiency promoted proliferation and metastasis. Moreover, transcriptome sequencing revealed that IL-1β downregulates the expression of matrix metalloproteinase 12 (MMP12). The signaling pathway involving MAPK/AP-1/MMP12 is involved in IL-1β-regulated ovarian cancer progression. Overall, we found that the proinflammatory cytokine IL-1β inhibits ovarian cancer cell viability and metastasis. These findings provided deeper insights into inflammation and cancer progression. Full article

The Bcl-2 family’s anti-apoptotic proteins, particularly Mcl-1, offer a viable avenue for cancer treatment since cancer cells can undergo apoptosis when their selective suppression occurs. Mcl-1 is essential for controlling the advancement of the cell cycle, as well as apoptosis. There is a constant clinical need for more potent treatments for breast and ovarian malignancies, even with advancements in the discovery of anticancer drugs. By synthesizing cyanopyrimidine derivatives that demonstrate both dual inhibitory activity against Mcl-1 and Bcl-2, and successful cell cycle arrest, our research seeks to contribute to the development of innovative therapeutic medicines. We created a number of new 6-substituted cyanopyrimidines and tested their anticancer effects on SKOV-3 and MCF-7 cell lines as well as apoptosis and cell cycle arrest assays. Full article

This study investigated whether combining niraparib and trabectedin in BRCA-proficient epithelial ovarian cancer induces deficiencies in ssDNA break repair and dsDNA homologous recombination, leading to synthetic lethality. A2780 and SKOV3 ovarian cancer cell lines were treated with niraparib and trabectedin. Cell viability was assessed using CCK-8 assays, while RT-qPCR and Western blot analyzed the expression of DNA repair and apoptosis-related genes. Apoptosis was evaluated via Annexin V/PI assays. The combination therapy exhibited a synergistic effect on A2780 cells but not on SKOV3 cells. Treatment reduced BRCA1, BRCA2, RAD51, PARP1, and PARP2 expression, indicating impaired DNA repair. γ-H2AX levels increased, suggesting DNA damage. The therapy also upregulated p53, PUMA, NOXA, BAX, BAK, and p21, promoting p53-mediated apoptosis and cell cycle arrest. Apoptosis induction was confirmed via Annexin V/PI assays. Silencing p53 with siRNA abolished all synergistic effects in A2780 cells. Niraparib and trabectedin combination therapy impairs DNA repair in BRCA-proficient ovarian cancer, leading to synthetic lethality through p53-dependent apoptosis. Full article