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Ovarian cancer is the fifth most prevalent cancer in women. Chemotherapy is a major treatment option for patients with advanced ovarian cancer (OC). Quinoline-2-thione and its derivatives are potential candidates for tumor therapy. In this study, we investigated the anticancer activity of the quinoline-2-thione derivative KA3D against ovarian cancer. The effect of KA3D on the viability of ovarian cancer cells was evaluated using MTT assay, and its effects on apoptosis and the cell cycle were detected using flow cytometry. Western blotting was performed to identify apoptosis-and cell cycle-related proteins altered by KA3D treatment. A xenograft model was used to verify the inhibitory effect of KA3D in vivo. H&E staining, biochemical indicator detection, and blood cell counts were used to observe the toxicity and side effects of KA3D. KA3D treatment impeded cell viability, induced apoptosis, and impeded the G2 phase of the cell cycle in ovarian cancer cells. Mechanistically, we found that KA3D enhanced the expression of proapoptotic molecules such as BAX and Caspase 3, while antiapoptotic proteins such as BCL2 were inhibited. The G0/G1 phase-related protein cyclin D1 was reduced and the G2 phase-related protein cyclin B1 was upregulated. In vivo, KA3D displayed potent anticancer activity, with no apparent toxicity in BABLC/c nude mice bearing SKOV3 cells. KA3D demonstrated remarkable chemotherapeutic drug efficacy in terms of significant cancer suppression in vitro and in vivo with low toxicity. [ABSTRACT FROM AUTHOR]

Background: Polysaccharides have various biological activities; the complexation of polysaccharides with trace element ions can produce synergistic effects, improving the original biological activities of sugars and trace elements. Methods: The preparation process of chitosan oligosaccharide selenium (COSSe) was optimized by the response surface method, followed by a detailed analysis of the resultant compound's characteristics. The anti-cancer activity of COSSe was studied using the human ovarian cancer cell line SKOV3 as a cell model. Results: The prepared COSSe response surface was well predicted, indicating successful chitosan oligosaccharide binding with selenium. Response surface method analyses identified the optimal synthesis conditions for COSSe: the reaction time of 5.08 h, the reaction temperature of 71.8 °C, and mass ratio (Na2SeO3: chitosan oligosaccharide) of 1.02. Under the optimal conditions, the final product, the selenium content, reached 1.302%. The results of cell experiments showed that COSSe significantly inhibited SKOV3 proliferation in a concentration-dependent manner. RNA-seq results showed that chitosan oligosaccharide and COSSe significantly modulated the expression of genes' DNA metabolic processes and cell cycle in SKOV3 cells. Gene enrichment analysis showed the inhibition of the cell cycle, and the results of flow cytometry showed that SKOV3 cells increased in the S phase and decreased in the G2/M phase, with a noted suppression in the protein expression of cyclin-dependent kinase 2 (CDK2) and cyclin A1 (CCNA1). Conclusion: COSSe has a stronger effect than chitosan oligosaccharide, leading to the arrest of the cell cycle in the S phase. Thus, COSSe may be an effective candidate for the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

The present study aimed to explore the effect of ultrasound-stimulated microbubble cavitation (USMC) on drug concentration and therapeutic efficacy of oral gefitinib in treating subcutaneously transplanted SKOV3 ovarian cancer tumors in nude mice. The present study employed the VINNO70 ultrasonic diagnostic and treatment integrated machine for USMC therapy. Firstly, the mechanical index was set at 0.25, and the therapeutic efficacy of USMC treatment was assessed at intervals of 5, 10 and 20 min. Briefly, 72 nude mice were randomized into the following four groups (n=18/group): Control group, USMC5 min group, USMC10 min group and USMC20 min group, and the therapeutic response to USMC treatment was evaluated by comparing pre-and post-intervention effects. Additionally, the combined therapeutic efficacy of USMC and gefitinib was investigated by randomly dividing 96 tumor-bearing mice into the following four groups (n=24/group): Control group, USMC group, gefitinib group and USMC + gefitinib group. Contrast-enhanced ultrasound, hematoxylin and eosin staining, western blotting, immunofluorescence staining, TUNEL staining, ELISA and liquid chromatography-mass spectrometry were performed in the present study. The results showed that USMC combined with gefitinib had the best treatment effect; the tumor inhibition rate was higher than that of gefitinib alone and the overall survival time was prolonged. In addition, the drug concentration in the tumor tissue obtained from the USMC + gefitinib group was revealed to be ~1.4 times higher than that detected in the group treated with gefitinib alone. The experimental results also confirmed that the strongest tumor inhibition rate and longest overall survival time was observed in the USMC + gefitinib group, followed by the gefitinib group and USMC group. STAT3 is an important signaling transducer and transcription factor, which, when phosphorylated, can lead to abnormal cell proliferation and malignant transformation. In addition, the upregulation of phosphorylated (p)-STAT3 is consider a reason for the poor efficacy of gefitinib in treating ovarian cancer. The present study revealed that ultrasound microbubble therapy could overcome this side effect. In conclusion, USMC improved the effects of oral gefitinib on subcutaneously transplanted SKOV3 ovarian cancer tumors in nude mice and increased drug penetration. In addition, USMC overcame the gefitinib-induced side effect of upregulated STAT3 phosphorylation and reduced the expression levels of p-STAT3 in the tumor. [ABSTRACT FROM AUTHOR]

Abstract Ovarian cancer is the fifth most prevalent cancer in women. Chemotherapy is a major treatment option for patients with advanced ovarian cancer (OC). Quinoline-2-thione and its derivatives are potential candidates for tumor therapy. In this study, we investigated the anticancer activity of the quinoline-2-thione derivative KA3D against ovarian cancer. The effect of KA3D on the viability of ovarian cancer cells was evaluated using MTT assay, and its effects on apoptosis and the cell cycle were detected using flow cytometry. Western blotting was performed to identify apoptosis-and cell cycle-related proteins altered by KA3D treatment. A xenograft model was used to verify the inhibitory effect of KA3D in vivo. H&E staining, biochemical indicator detection, and blood cell counts were used to observe the toxicity and side effects of KA3D. KA3D treatment impeded cell viability, induced apoptosis, and impeded the G2 phase of the cell cycle in ovarian cancer cells. Mechanistically, we found that KA3D enhanced the expression of proapoptotic molecules such as BAX and Caspase 3, while antiapoptotic proteins such as BCL2 were inhibited. The G0/G1 phase-related protein cyclin D1 was reduced and the G2 phase-related protein cyclin B1 was upregulated. In vivo, KA3D displayed potent anticancer activity, with no apparent toxicity in BABLC/c nude mice bearing SKOV3 cells. KA3D demonstrated remarkable chemotherapeutic drug efficacy in terms of significant cancer suppression in vitro and in vivo with low toxicity.

Abstract Background High-grade serous ovarian cancer (HGSOC) is a common gynecologic malignancy with a poor prognosis. The traditional Chinese medicine formula Erzhimaoling decoction (EZMLD) has anticancer potential. This study aims to elucidate the anticancer effects of EZMLD on HGSOC in vitro and in vivo. Materials and methods EZMLD-containing serum was prepared from Sprague–Dawley rats for treating SKOV3 ovarian cancer cells at varying concentrations for 24 h and 48 h to determine the IC50. Concentrations of 0%, 5%, and 10% for 24 h were chosen for subsequent in vitro experiments. The roles of METTL3 and METTL14 in SKOV3 cells were explored by overexpressing these genes and combining EZMLD with METTL3/14 knockdown. Investigations focused on cell viability and apoptosis, apoptosis-related protein expression, and KRT8 mRNA m6A modification. For in vivo studies, 36 BALB/c nude mice were divided into six groups involving EZMLD (6.75, 13.5, and 27 g/kg) and METTL3 or METTL14 knockdowns, with daily EZMLD gavage for two weeks. Results In vitro, EZMLD-containing serum had IC50 values of 8.29% at 24 h and 5.95% at 48 h in SKOV3 cells. EZMLD-containing serum decreased SKOV3 cell viability and increased apoptosis. EZMLD upregulated METTL3/14 and FAS-mediated apoptosis proteins, while downregulating Keratin 8 (KRT8). EZMLD increased KRT8 mRNA m6A methylation. METTL3/14 overexpression reduced SKOV3 cell viability and increased apoptosis, while METTL3/14 knockdown mitigated EZMLD's effects. In vivo, EZMLD suppressed SKOV3 xenografts growth, causing significant apoptosis and modulating protein expression. Conclusions EZMLD has therapeutic potential for ovarian cancer and may be considered for other cancer types. Future research may explore its broader effects beyond cell apoptosis.

Efficacies of plant metabolites are known to be dependent on their extraction methods. Yields and compositions of phytoconstituents in the extract were evaluated following supercritical fluid extraction (SFE) of Vitex agnus-castus leaves, static extraction times (SET) for 30 min, subsequently dynamic extraction time (DET) for 30 min (condition A) and SET for 0 min followed by DET for 60 min (condition B). The extract exposed to condition B gave an extraction yield of 0.169 g compared to 0.115 g for condition A. High-performance liquid chromatography analysis revealed compounds including cinnamic acid, kaempferol, ferulic acid, rutin, and caffeic acid, in high concentrations in the extract exposed to condition B. Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterococcus faecalis, and Candida albicans were more affected by the condition B with 32 ± 0.1, 20 ± 0.2, 32 ± 0.2, 35 ± 0.2, and 40 ± 0.1 mm inhibition zones, respectively. Less MIC and MBC were noticed of the exposed extract to condition B than to condition A against C. albicans and bacteria. The IC50 of the extract exposed to condition B was high against ovarian tumor cells. Presently the efficacy of the exposed extract to condition B for wound healing process was documented.

Background Ovarian cancer management has not yet given a satisfactory result, and the recurrence rate is still high. One of the reasons for this is resistance to chemotherapy. Melatonin and cisplatin may be involved in the chemotherapy resistance of ovarian cancer. Methods A laboratory experiment was performed using melatonin and cisplatin in the SKOV3 cell, from September 2020 to November 2021 at the SCTE and Integrated Laboratory & Research Center Universitas Indonesia. Several variables were used, such as doxorubicin, melatonin, cisplatin, and combination of cisplatin and melatonin at several concentrations (1×, 3/4×, 1/2×, and 1/4×). A total of 24 samples were included and divided into 8 groups. The IC50 values of melatonin, doxorubicin, and cisplatin as well as cell viability was calculated via MTS assay. Subsequently, flow cytometry was performed to assess the effect of cisplatin and melatonin on the mechanisms of CTR1, p-glycoprotein, GSH, ERCC1, e-cadherin, and apoptosis. Analysis of variance and Bonferroni test were employed for the study. Results The IC50 values of melatonin, cisplatin, and doxorubicin were 1.841 mM, 117.5 mM, and 14.72 mM, respectively. The combination groups of cisplatin and melatonin reduced cell viability; decreased the CTR1 mean (19.73), Pgp (6.7), GSH (11.73), and ERCC1 (4.27) in the combination 1 (C1) group; and increased e-cadherin (32.2) and annexin V (53.57) also in the combination 1 (C1) group. Conclusions The combination of melatonin and cisplatin might have an impact on drug resistance via several mechanisms in ovarian cancer.

Background: High-grade serous ovarian cancer (HGSOC) is a common gynecologic malignancy with a poor prognosis. The traditional Chinese medicine formula Erzhimaoling decoction (EZMLD) has anticancer potential. This study aims to elucidate the anticancer effects of EZMLD on HGSOC in vitro and in vivo. Materials and methods: EZMLD-containing serum was prepared from Sprague–Dawley rats for treating SKOV3 ovarian cancer cells at varying concentrations for 24 h and 48 h to determine the IC50. Concentrations of 0%, 5%, and 10% for 24 h were chosen for subsequent in vitro experiments. The roles of METTL3 and METTL14 in SKOV3 cells were explored by overexpressing these genes and combining EZMLD with METTL3/14 knockdown. Investigations focused on cell viability and apoptosis, apoptosis-related protein expression, and KRT8 mRNA m6A modification. For in vivo studies, 36 BALB/c nude mice were divided into six groups involving EZMLD (6.75, 13.5, and 27 g/kg) and METTL3 or METTL14 knockdowns, with daily EZMLD gavage for two weeks. Results: In vitro, EZMLD-containing serum had IC50 values of 8.29% at 24 h and 5.95% at 48 h in SKOV3 cells. EZMLD-containing serum decreased SKOV3 cell viability and increased apoptosis. EZMLD upregulated METTL3/14 and FAS-mediated apoptosis proteins, while downregulating Keratin 8 (KRT8). EZMLD increased KRT8 mRNA m6A methylation. METTL3/14 overexpression reduced SKOV3 cell viability and increased apoptosis, while METTL3/14 knockdown mitigated EZMLD's effects. In vivo, EZMLD suppressed SKOV3 xenografts growth, causing significant apoptosis and modulating protein expression. Conclusions: EZMLD has therapeutic potential for ovarian cancer and may be considered for other cancer types. Future research may explore its broader effects beyond cell apoptosis. [ABSTRACT FROM AUTHOR]

Efficacies of plant metabolites are known to be dependent on their extraction methods. Yields and compositions of phytoconstituents in the extract were evaluated following supercritical fluid extraction (SFE) of Vitex agnus-castus leaves, static extraction times (SET) for 30 min, subsequently dynamic extraction time (DET) for 30 min (condition A) and SET for 0 min followed by DET for 60 min (condition B). The extract exposed to condition B gave an extraction yield of 0.169 g compared to 0.115 g for condition A. High-performance liquid chromatography analysis revealed compounds including cinnamic acid, kaempferol, ferulic acid, rutin, and caffeic acid, in high concentrations in the extract exposed to condition B. Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterococcus faecalis, and Candida albicans were more affected by the condition B with 32 ± 0.1, 20 ± 0.2, 32 ± 0.2, 35 ± 0.2, and 40 ± 0.1 mm inhibition zones, respectively. Less MIC and MBC were noticed of the exposed extract to condition B than to condition A against C. albicans and bacteria. The IC50 of the extract exposed to condition B was high against ovarian tumor cells. Presently the efficacy of the exposed extract to condition B for wound healing process was documented. [ABSTRACT FROM AUTHOR]

Abstract Background Ginger is a common aromatic vegetable with a wide range of functional ingredients and considerable medicinal and nutritional properties. Numerous studies have shown that ginger and its active ingredients have suppressive effects on manifold tumours, including ovarian cancer (OC). However, the molecular mechanism by which ginger inhibits OC is not clear. The aim of this study was to investigate the function and mechanism of ginger in OC. Methods The estimation of n6-methyladenosine (m6A) levels was performed using the m6A RNA Methylation Quantification Kit, and RT-qPCR was used to determine the expression of m6A-related genes and proteins. The m6A methylationome was detected by MeRIP-seq, following analysis of the data. Differential methylation of genes was assessed utilizing RT-qPCR and Western Blotting. The effect of ginger on SKOV3 invasion in ovarian cancer cells was investigated using the wound healing assay and transwell assays. Results Ginger significantly reduced the m6A level of OC cells SKOV3. The 3’UTR region is the major site of modification for m6A methylation, and its key molecular activities include Cell Adhesion Molecules, according to meRIP-seq results. Moreover, it was observed that Ginger aids significantly in downregulating the CLDN7, CLDN11 mRNA, and protein expression. The results of wound healing assay and transwell assay showed that ginger significantly inhibited the invasion of OC cells SKOV3. Conclusions Ginger inhibits ovarian cancer cells’ SKOV3 invasion by regulating m6A methylation through CLDN7, CLDN11, and CD274.

Background Ovarian cancer management has not yet given a satisfactory result, and the recurrence rate is still high. One of the reasons for this is resistance to chemotherapy. Melatonin and cisplatin may be involved in the chemotherapy resistance of ovarian cancer. Methods A laboratory experiment was performed using melatonin and cisplatin in the SKOV3 cell, from September 2020 to November 2021 at the SCTE and Integrated Laboratory & Research Center Universitas Indonesia. Several variables were used, such as doxorubicin, melatonin, cisplatin, and combination of cisplatin and melatonin at several concentrations (1×, 3/4×, 1/2×, and 1/4×). A total of 24 samples were included and divided into 8 groups. The IC50 values of melatonin, doxorubicin, and cisplatin as well as cell viability was calculated via MTS assay. Subsequently, flow cytometry was performed to assess the effect of cisplatin and melatonin on the mechanisms of CTR1, p-glycoprotein, GSH, ERCC1, e-cadherin, and apoptosis. Analysis of variance and Bonferroni test were employed for the study. Results The IC50 values of melatonin, cisplatin, and doxorubicin were 1.841 mM, 117.5 mM, and 14.72 mM, respectively. The combination groups of cisplatin and melatonin reduced cell viability; decreased the CTR1 mean (19.73), Pgp (6.7), GSH (11.73), and ERCC1 (4.27) in the combination 1 (C1) group; and increased e-cadherin (32.2) and annexin V (53.57) also in the combination 1 (C1) group. Conclusions The combination of melatonin and cisplatin might have an impact on drug resistance via several mechanisms in ovarian cancer.

The reaction of copper(II) acetate with 2-furancarboxylic (HFur)/5-nitro-2-furancarboxylic (HNfur) acids and 5-nitro-1,10-phenanthroline (Nphen) in methanol resulted in the formation of the binuclear coordination compounds [Cu2(L)4(Nphen)2]·X (L = Fur (I), Nfur (II); X = H2O (I)), which were structurally studied by direct X-ray diffraction (CCDC no. 2244205 (I) and 2244206 (II)). According to X-ray diffraction data, the coordination environment of the central metal ion in I and II is composed of two nitrogen atoms of Nphen and three oxygen atoms of the acid anions, which thus form the {CuN2O3} tetragonal pyramid in which the copper coordination number is five. Intermolecular hydrogen bonds and stacking interactions between the Nphen aromatic rings provide supramolecular stabilization of I and II. A characteristic feature of supramolecular organization of II is the presence of a coordination bond between the Cu2+ cation and oxygen of the Nphen group of parallel chains. A biological activity assay for complexes I and II concerning the cytotoxic properties against a human ovarian adenocarcinoma cell line (SKOV3) and the mycobacterial strain Mycolicibacterium smegmatis showed an efficient suppression of cell viability. The results of mathematical modeling of the probability of Cu2+ binding to amino acid residues of M. smegmatis proteins suggested the affinity of the Cu(II) ion to a number of amino acids in polypeptide sites. It was shown that metal ion binding in mycobacterial proteins is more characteristic of histidine- and glutamic acid-containing moieties. [ABSTRACT FROM AUTHOR]

Garlic is known to be rich in antioxidants, inhibit the proliferation of various cancer cells, and hamper cancer formation and growth, but various forms of garlic can differ greatly in these respects. This study aimed to compare the antioxidant properties of acetone, ethanol, and aqueous extracts of fresh Polish and Spanish garlic, black and granulated garlic, as well as fresh and dried ramsons. Extracts of black and granulated garlic showed the lowest total antioxidant capacity (TAC). The content of phenolic compounds correlated with TAC measured by ABTS• decolorization and FRAP methods, and with the results of FRAP and DPPH• decolorization assays. Garlic extracts inhibited the proliferation of PEO1 and SKOV3 ovarian cancer cells and, usually to a smaller extent, MRC-5 fibroblasts. PBS extracts of fresh Spanish garlic showed the highest potency for inhibition of proliferation of PEO1 cells (IC50 of 0.71 µg extract dry mass/100 µL medium). No significant correlation was found between the potency for inhibition of proliferation and the content of phenolics or flavonoids, confirming that phenolics are the main determinants of TAC but do not contribute significantly to the antiproliferative effects of garlic. [ABSTRACT FROM AUTHOR]

Heat shock protein 27 (Hsp27) is an important member of the chaperone protein family and its overexpression promotes cancer cell survival. Here, we investigated the apoptosis inducer role of the J2 compound (Hsp27 inhibitor) in human ovarian cancer cell lines (SKOV3 and OVCAR-3). Cell proliferation was measured by MTT assay. The parameters of J2-Hsp27 interaction were determined with molecular docking calculation. The inhibitory effect of the J2 compound on Hsp27 chaperone activity was investigated by luciferase activity assay. Finally, the apoptotic inducer role of the J2 compound on SKOV3 and OVCAR-3 cells was determined by RT-PCR and caspase-3 activity assay. J2 compound decreased SKOV3 and OVCAR-3 cell proliferation in a dose-dependent manner at 48 h with IC50 values of 17.34 µM and 12.63 µM, respectively. J2 inhibited the refolding process of denatured luciferase as an Hsp27 inhibitor. Molecular docking calculation was carried out to determine the interaction between Hsp27 and J2. The results indicated that J2 selectively binds to the phosphorylation site of the Hsp27 and inhibits the phosphorylation process of Hsp27. To determine the apoptotic potential of the J2 compound against ovarian cancer cells, the mRNA expression levels of apoptotic and antiapoptotic markers (Bax, Bcl-2, Bcl-xL, Cyt-c, p53, Apaf-1, Cas-3, Cas-8, Cas-9, TNF-α, DAXX, and Ask-1) were measured using RT-PCR. While J2 increased the expressions of apoptotic genes, it decreased the expressions of anti-apoptotic genes. Further, the J2 compound increased Cas-3 activity in SKOV3 and OVCAR-3 at 5.52 and 4.12 folds, respectively. These results confirm that J2 has great potential and significance in the stimulation of apoptosis in ovarian cancer cells as an Hsp27 inhibitor. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is most common in women of reproductive age, giving rise to androgen excess and anovulation, leading to infertility and non‐reproductive complications. We explored the ameliorating effect of naringenin in PCOS using the Sprague Dawley (SD) rat model and human granulosa cells. Letrozole‐induced PCOS rats were given either naringenin (50 mg/kg/day) alone or in combination with metformin (300 mg/kg/day), followed by the estrous cycle, hormonal analysis, and glucose sensitivity test. To evaluate the effect of naringenin on granulosa cell (hGC) steroidogenesis, we treated cells with naringenin (2.5 μM) alone or in combination with metformin (1 mM) in the presence of forskolin (10 μM). To determine the steroidogenesis of CYP‐17A1, ‐19A1, and 3βHSD2, the protein expression levels were examined. Treatment with naringenin in the PCOS animal groups increased ovulation potential and decreased cystic follicles and levels of androgens. The expression levels of CYP‐17A1, ‐19A1, and 3βHSD2, were seen restored in the ovary of PCOS SD rats' model and in the human ovarian cells in response to the naringenin. We found an increased expression level of phosphorylated‐AKT in the ovary and hGCs by naringenin. Naringenin improves ovulation and suppress androgens and cystic follicles, involving AKT activation. [ABSTRACT FROM AUTHOR]

Background: Lotus root polysaccharide is a natural antioxidant. As a new anticancer drug, it has anti-proliferation and pro-apoptotic effects in a variety of tumour cells, but its effect on ovarian cancer is not clear. In study, we attempted to elucidate the role and mechanism of lotus root polysaccharide in SKOV3 cells. Methods: In this study, the effect of lotus root polysaccharide on mRNA of SKVO3 cells was analyzed by RNA-seq, and verified by Western blot, flow cytometry, fluorescence detection and other techniques. Results: The results showed that lotus root polysaccharide could inhibit the proliferation of ovarian cancer cells. Then, a change in gene expression was found by RNA-seq. In the mRNA (differentially expressed mRNA) with these differences, significant changes in the cell cycle were found by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Subsequently, the proportion of cells in S phase decreases and G2/M phase increases, as seen with propidium iodide staining. Gene Set Enrichment Analysis showed inhibition of the cell cycle, and the gene and protein expression of CDK1, CCNA1 and CCNB1 were inhibited. Conclusion: Our results show that lotus root polysaccharide can inhibit the growth of SKOV3 cells in vitro by blocking the cell cycle at the G2/M phase, which reveals the potential of lotus root polysaccharide in the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Progestin-only based oral contraceptives are majorly used as 'minipill' to prevent unintended pregnancy and treat conditions like polycystic ovary syndrome, hirsutism, and acne. However, the dearth of literature has constrained our comprehension of the exogenous progestin in relation to ovarian cancer progression. Therefore, the aim of the present study was to evaluate the chemo-preventive potential of synthetic progestin Norethindrone (NET) in epithelial ovarian cancer in vitro. Briefly, SKOV3 cells were treated with 1, 10 and 100 µM concentrations of NET for seven days period. The assays for cell viability, wound-healing, cell cycle progression, detection of reactive oxygen species (ROS) and apoptosis were executed to illustrate the protective role of NET. To further clarify the underlying process, quantitative analysis of mRNA levels of oncogenes linked to angiogenesis, inflammation, proliferation, and metastasis (VEGF, HIF-1α, COX-2, and PGRMC1) and tumour suppressor (TP53) genes was conducted. Our study revealed that NET treatment significantly reduced SKOV3 cell growth by inducing cell cycle arrest at G2/M phase, elevating ROS levels, triggering cell death via apoptosis and necrosis, and inhibiting cell migration in a dose-dependent manner. Notably, NET also upregulated TP53 expression while concurrently downregulating VEGF, HIF-1α, COX-2, and PGRMC1 expression. Our results demonstrated that the chemo-preventive effect of Norethindrone may originate from the interaction of genes which exert a protective effect against ovarian carcinogenesis. The current findings also support further investigation, which may lead to changes in prescription practices or health-related advice for women. [ABSTRACT FROM AUTHOR]

Background/aim: The study aims to profile the dual-specificity phosphatases (DUSP) expression in response to Transforming growth factor β1 (TGFβ1)-induced epithelial-mesenchymal transition (EMT) in ovarian adenocarcinoma cells. Materials and methods: The ovarian adenocarcinoma cell line SKOV3 was used as a TGFβ1-induced EMT model. Cells were incubated with 5 ng/mL TGFβ1 to induce EMT. EMT was confirmed with real-time qPCR, western blot, and immunofluorescence analyses of various EMT markers. Western blot was used to analyze phospho- and total MAPK protein levels. Typical and atypical DUSPs mRNA expression profile was determined by real-time qPCR. Results: The epithelial marker E-cadherin expressions were decreased and mesenchymal EMT markers Snail and Slug expression levels were increased after TGFβ1 induction. Phosphorylation of ERK1/2 and p38 MAPK were enhanced in response to TGFβ1 treatment. The expression of DUSP2, DUSP6, DUSP8, DUSP10, and DUSP13 were decreased while DUSP7, DUSP16, DUSP18, DUSP21, and DUSP27 were increased by TGFβ1. Conclusion: TGFβ1 induced EMT which was accompanied by increased activity of MAPKs, and led to marked changes in expressions of several DUSPs in SKOV3 cells. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer management has not yet given a satisfactory result, and the recurrence rate is still high. One of the reasons for this is resistance to chemotherapy. Melatonin and cisplatin may be involved in the chemotherapy resistance of ovarian cancer. Methods: A laboratory experiment was performed using melatonin and cisplatin in the SKOV3 cell, from September 2020 to November 2021 at the SCTE and Integrated Laboratory & Research Center Universitas Indonesia. Several variables were used, such as doxorubicin, melatonin, cisplatin, and combination of cisplatin and melatonin at several concentrations (1×, 3/4×, 1/2×, and 1/4×). A total of 24 samples were included and divided into 8 groups. The IC50 values of melatonin, doxorubicin, and cisplatin as well as cell viability was calculated via MTS assay. Subsequently, flow cytometry was performed to assess the effect of cisplatin and melatonin on the mechanisms of CTR1, p-glycoprotein, GSH, ERCC1, e-cadherin, and apoptosis. Analysis of variance and Bonferroni test were employed for the study. Results: The IC50 values of melatonin, cisplatin, and doxorubicin were 1.841 mM, 117.5 mM, and 14.72 mM, respectively. The combination groups of cisplatin and melatonin reduced cell viability; decreased the CTR1 mean (19.73), Pgp (6.7), GSH (11.73), and ERCC1 (4.27) in the combination 1 (C1) group; and increased e-cadherin (32.2) and annexin V (53.57) also in the combination 1 (C1) group. Conclusions: The combination of melatonin and cisplatin might have an impact on drug resistance via several mechanisms in ovarian cancer.

Abstract Background Serous ovarian carcinoma is the most common type of ovarian carcinoma. Tumor-associated macrophages (TAMs) promote ovarian cancer progression. Most macrophages are generated by monocyte differentiation. Lysophosphatidic acid (LPA) levels are high in blood, tissues and ascites of patients with ovarian cancer. This study investigated whether human monocytes can directly differentiate into TAMs in the serous ovarian carcinoma microenvironment. Methods Human monocytes were isolated and purified from umbilical cord blood. A serous ovarian carcinoma-like microenvironment was generated by coculturing monocytes and SKOV3 cells in 0.4-μm-pore-size Transwell chambers. Additionally, the effect of LPA was assessed. The two cultured cell types and supernatants were evaluated. Results The morphology and function of monocytes cocultured with SKOV3 cells and/or stimulated with LPA were significantly changed compared with those of non-stimulated monocytes. The CD14 + CD163 + and CD206 + phenotype indicated that stimulated cells were TAMs. The induced cells promoted SKOV3 cell proliferation and invasion, further proving that they were TAMs. The level of the cytokine interleukin-6R in the supernatant was significantly elevated in the treatment groups compared to the control monocyte group. Pathway enrichment analysis of ELISA results showed a strong influence of interleukin-6 family signaling, especially the JAK-STAT signaling pathway, further confirming the importance of IL-6R. Conclusion Monocytes can differentiate into TAMs under coculture with SKOV3 cells and/or LPA stimulation. The induced TAMs promote SKOV3 cell proliferation and invasion. The cytokine receptor IL-6sR and the JAK-STAT signaling pathway play an important role in the differentiation of monocytes into TAMs.

The repurposing strategy of converting nimesulide from an anti-fever drug to an anti-cancer agent by modifying its main structure targeting HSP27 is gaining great attention these days. The goal of this study focuses on synthesizing a new nimesulide derivative with new ligands that have biological anti-cancer activities in different cancer models using the in-vitro assay. Nimesulide derivative L1 was synthesized, characterized by 1H NMR, 13C NMR, FTIR, melting point, mass spectra, and TGA analysis. A single crystal was diffracted and showed colorless block group P-1. The results revealed that L1 demonstrates potent anti-cancer activity with lung (H292), ovarian (SKOV3), and breast (SKBR3) cancer cell lines in-vitro models with IC50 values below 8.8 µM.

Introduction: MicroRNAs (miRNAs) are short-sequence RNAs that regulate gene expression by targeting messenger RNAs (mRNAs). Recent studies reveal that miRNA-324-5p plays an important role in worsening the ovarian cancer prognosis when the expression is very high. This study aimed to develop a miRNA targeted therapy by targeting the miRNA-324-5p function as a miRNA-324-5p inhibitor. Methods: Chitosan nanoparticles were used for antimiRNA-324-5p delivery into SKOV3 cell lines formulated by ionic gelation method. Antiproliferative effect of CS-NPs-antimiRNA was assessed by the MTT Assay. A mechanism study assessed the anticancer effect of the formula. In silico analysis used miRTar.Human and StarmiRDB combined with Genecard to predict the target genes of antimiR. Hawkdock web server was used to analyze protein-protein interactions that were further validated by quantitative polymerase chain reaction (qPCR). Results: The results of qPCR analysis showed endogenous miRNA-324-5p decreased after 24-hour transfection of antagonist miRNA. Furthermore, the MTT assay results showed that antimiRNA was able to inhibit SKOV3 cell proliferation (80 nM 68.13%, P

Garlic is known to be rich in antioxidants, inhibit the proliferation of various cancer cells, and hamper cancer formation and growth, but various forms of garlic can differ greatly in these respects. This study aimed to compare the antioxidant properties of acetone, ethanol, and aqueous extracts of fresh Polish and Spanish garlic, black and granulated garlic, as well as fresh and dried ramsons. Extracts of black and granulated garlic showed the lowest total antioxidant capacity (TAC). The content of phenolic compounds correlated with TAC measured by ABTS• decolorization and FRAP methods, and with the results of FRAP and DPPH• decolorization assays. Garlic extracts inhibited the proliferation of PEO1 and SKOV3 ovarian cancer cells and, usually to a smaller extent, MRC-5 fibroblasts. PBS extracts of fresh Spanish garlic showed the highest potency for inhibition of proliferation of PEO1 cells (IC50 of 0.71 µg extract dry mass/100 µL medium). No significant correlation was found between the potency for inhibition of proliferation and the content of phenolics or flavonoids, confirming that phenolics are the main determinants of TAC but do not contribute significantly to the antiproliferative effects of garlic.

Background and purpose: Ovarian cancer is one of the leading causes of cancer mortality in women. Despite the increase in cases of this cancer, the current therapeutic strategy is not effective. This study aimed to investigate the effect of cisplatin (Cis) with alantolactone (ALT) and ZnO nanoparticles (ZnONPs) in inducing apoptosis in SKOV3 ovarian cancer cells line. Experimental approach: To evaluate the viability of SKOV3 cells and determine the IC50 of Cis, ALT, and ZnONPs, MTT assay was used. Real-time PCR and western blotting were used to evaluate the expression levels of genes (XIAP, cyclin D1, Bcl-2, Bax, and MDM2) and proteins (XIAP, cyclin D1, Bcl-2, Bax), respectively. Also, cellular ROS levels were assessed by fluorimetry. Findings / Results: Our results showed that ALT and ZnONPs significantly increased the response to Cis in SKOV3 cells compared to the control and this response is remarkably increased in the triple combination (ALT-Cis-ZnONPs). The expression of XIAP, cyclin D1, and Bcl-2 genes and proteins in the groups treated with ALT, Cis, and ZnONPs as a single agent, double and triple combination were significantly reduced compared to the control, while Bax was generally shown an increase. Also, the level of intracellular ROS is higher in the treatment groups than in the control group and the highest increase was observed in the triple combination. Conclusion and implications: Taken together, our data demonstrated the potential therapeutic approach of using ALT and ZnONPs that may enhance the apoptotic effects of Cis on the SKOV3 cells.

Salvia triloba (S. triloba) is an herb inherently linked to traditional medicine systems in the Eastern Mediterranean region. There is minimal experimental evidence however, regarding the anticancer effects of S. triloba in both osteosarcoma and ovarian cancer. In this study, we investigated the effects of crude (macerated) S. triloba ethanol and acetone leaf extracts on viability, migratory ability, and the expression of genes regulating these activities in U2OS and SKOV3 cells using MTT assay, scratch-wound healing/trans-well migration assay, and RT-qPCR respectively. MTT assay results indicated that the acetone extract significantly reduced both U2OS and SKOV3 cell viability with half-maximal inhibitory concentrations (IC50) of 54.51 ± 1.10 µg/mL and 75.96 ± 1.0237 µg/mL respectively; these concentrations further displayed negligible hemolytic activity. The combination of acetone extract (19 µg/mL) and paclitaxel (0.787 µg/mL) displayed synergy and reduced SKOV3 cell viability by over 90%. Additionally, the trans-well migration assay illustrated that the acetone extract (IC50) inhibited both U2OS and SKOV3 cell migration by more than 50%. Moreover, S. triloba acetone extract significantly downregulated the steady-state mRNA expression of key genes involved in driving select cancer hallmarks. Four fractions were generated from the acetone extract by thin layer chromatography (TLC), and the obtained retention factors (Rf) (ranging from 0.2 to 0.8) suggested a mixture of high and moderately polar compounds whose bioactivities require further investigation. In addition, FTIR measurements of the extract revealed peaks corresponding to OH, aliphatic CH, and ester groups suggesting the presence of phenolic compounds, terpenes, and polysaccharides. Altogether, these results suggest that S. triloba possesses potential therapeutic compounds that inhibit cell proliferation and migration, and modulate several genes involved in osteosarcoma and ovarian carcinoma progression. [ABSTRACT FROM AUTHOR]

Background: Serous ovarian carcinoma is the most common type of ovarian carcinoma. Tumor-associated macrophages (TAMs) promote ovarian cancer progression. Most macrophages are generated by monocyte differentiation. Lysophosphatidic acid (LPA) levels are high in blood, tissues and ascites of patients with ovarian cancer. This study investigated whether human monocytes can directly differentiate into TAMs in the serous ovarian carcinoma microenvironment. Methods: Human monocytes were isolated and purified from umbilical cord blood. A serous ovarian carcinoma-like microenvironment was generated by coculturing monocytes and SKOV3 cells in 0.4-μm-pore-size Transwell chambers. Additionally, the effect of LPA was assessed. The two cultured cell types and supernatants were evaluated. Results: The morphology and function of monocytes cocultured with SKOV3 cells and/or stimulated with LPA were significantly changed compared with those of non-stimulated monocytes. The CD14 + CD163 + and CD206 + phenotype indicated that stimulated cells were TAMs. The induced cells promoted SKOV3 cell proliferation and invasion, further proving that they were TAMs. The level of the cytokine interleukin-6R in the supernatant was significantly elevated in the treatment groups compared to the control monocyte group. Pathway enrichment analysis of ELISA results showed a strong influence of interleukin-6 family signaling, especially the JAK-STAT signaling pathway, further confirming the importance of IL-6R. Conclusion: Monocytes can differentiate into TAMs under coculture with SKOV3 cells and/or LPA stimulation. The induced TAMs promote SKOV3 cell proliferation and invasion. The cytokine receptor IL-6sR and the JAK-STAT signaling pathway play an important role in the differentiation of monocytes into TAMs. [ABSTRACT FROM AUTHOR]

The repurposing strategy of converting nimesulide from an anti-fever drug to an anti-cancer agent by modifying its main structure targeting HSP27 is gaining great attention these days. The goal of this study focuses on synthesizing a new nimesulide derivative with new ligands that have biological anti-cancer activities in different cancer models using the in-vitro assay. Nimesulide derivative L1 was synthesized, characterized by 1H NMR, 13C NMR, FTIR, melting point, mass spectra, and TGA analysis. A single crystal was diffracted and showed colorless block group P-1. The results revealed that L1 demonstrates potent anti-cancer activity with lung (H292), ovarian (SKOV3), and breast (SKBR3) cancer cell lines in-vitro models with IC 50 values below 8.8 µM. [ABSTRACT FROM AUTHOR]

Cu2O as a new heterogeneous green nanocatalyst is biosynthesized from Cressa leaf extract and characterized by some techniques including XRD, FTIR, UV–Vis, SEM, and TEM. Then, the prepared nanocatalyst was applied in the synthesis of some chromeno[4,3-b]chromenes under aerobic conditions. Reusability studies warrant acceptable reproducibility of the nanomaterial. Low reaction time, easy workup, cost-effectiveness, wide substrate scope, good to excellent yield, and complete atom economy are significant features of this new method. At the final part of this study, the in vitro cellular toxicity of Cu2O nanoparticles is examined on SKOV3 human ovarian carcinoma cell line via an MTT assay. The reduction in cell viability proved the cytotoxicity of the nanoparticles toward the performed ovarian cancer cell line. [ABSTRACT FROM AUTHOR]

Targeted drug conjugates based on Affibody molecules fused to an albumin-binding domain (ABD) for half-life extension have demonstrated potent anti-tumor activity in preclinical therapeutic studies. Furthermore, optimization of their molecular design might increase the cytotoxic effect on tumors and minimize systemic toxicity. This study aimed to investigate the influence of length and composition of a linker between the human epidermal growth factor receptor 2 (HER2)-targeted affibody molecule (ZHER2:2891) and the ABD domain on functionality and biodistribution of affibody-drug conjugates containing a microtubulin inhibitor mertansin (mcDM1) (AffiDCs). Two conjugates, having a trimeric (S3G)3 linker or a trimeric (G3S)3 linker were produced, radiolabeled with 99mTc(CO)3, and compared side-by-side in vitro and in vivo with the original ZHER2:2891-G4S-ABD-mcDM1 conjugate having a monomeric G4S linker. Both conjugates with longer linkers had a decreased affinity to HER2 and mouse and human serum albumin in vitro, however, no differences in blood retention were observed in NMRI mice up to 24 h post injection. The use of both (S3G)3 and (G3S)3 linkers reduced liver uptake of AffiDCs by approximately 1.2-fold compared with the use of a G4S linker. This finding provides important insights into the molecular design for the development of targeted drug conjugates with reduced hepatic uptake. [ABSTRACT FROM AUTHOR]

Nanoparticles such as carbon nanotubes (CNTs) have various clinical and diagnostic applications as utilised for imaging and drug delivery. Therapeutic proteins/peptides can be loaded on CNT coronas to specifically hit immune cells in overdrive or uncontrolled malignant cells. Previously, it was reported that a recombinant version of human surfactant protein D (rfhSP-D) containing trimeric C-type lectin domains induced apoptosis in several tumour cells/cell lines, including SKOV3, which is an ovarian tumour cell line. Solid-phase rfhSP-D coated on a microtiter plate is considerably more potent in inducing apoptosis in breast tumour cells. We have immobilised highly purified, endotoxin-free rfhSP-D on CNTs and assessed its antiproliferative effect on SKOV3 cells. Biotinylated rfhSP-D-CNTs were phagocytosed by SKOV3 cells, followed by apoptosis in a time-dependent manner. Gene expression analysis revealed compromised mTOR complex as a mechanism of apoptosis. When rfhSP-D-CNTs were added to a culture system of SKOV3 cells, it produced a highly proinflammatory immune response that is likely anti-tumorigenic. Thus, rfhSP-D-CNT seems a worthwhile nanocarrier for testing in vivo using an animal model of orthotopic ovarian cancer.

A N-glycan specific lectin from Rhizoctonia bataticola [RBL] was shown to induce growth inhibitory and apoptotic effect in human ovarian, colon and leukemic cells but mitogenic effect on normal PBMCs as reported earlier, revealing its clinical potential. RBL has unique specificity for high mannose tri and tetra antennary N-glycans, expressed in ovarian cancer and also recognizes glycans which are part of CA 125 antigen, a well known ovarian cancer marker. Hence, in the present study diagnostic and therapeutic potential of RBL was investigated using human ovarian epithelial cancer SKOV3 and OVCAR3 cells known for differentially expressing CA 125. RBL binds differentially to human ovarian normal, cyst and cancer tissues. Flow cytometry, western blot analysis of membrane proteins showed the competitive binding of RBL and CA 125 antibody for the same binding sites on SKOV3 and OVCAR3 cells. RBL has strong binding to both SKOV3 and OVCAR3 cells with MFI of 173 and 155 respectively. RBL shows dose and time dependent growth inhibitory effect with IC50 of 2.5 and 8 μg/mL respectively for SKOV3 and OVCAR3 cells. RBL induces reproductive cell death, morphological changes, nuclear degradation and increased release of ROS in SKOV3 and OVCAR3 cells leading to cell death. This is also supported by increase in hypodiploid population, altered MMP leading to apoptosis possibly involving intrinsic pathway. Adhesion, wound healing, invasion and migration assays demonstrated anti-metastasis effect of RBL apart from its growth inhibitory effect. These results show the promising potential of RBL both as a diagnostic and therapeutic agent. [ABSTRACT FROM AUTHOR]

Purpose: Ovarian cancer is the most lethal of gynecological malignancies. Recently, the development of microRNA (miRNA) -based therapeutics that could impact broad cellular programs, leading to inhibition of cancer cell viability, is gaining attention in the therapeutic landscape. The therapy is based on the presence of aberrant expressions of miRNA in cancer cells. Decreasing of tumor suppressor miRNA expression causes upregulation of oncoprotein, which worsens the prognosis of the ovarian cancer. Methods: miR-155-5p mimics were carried by chitosan nanoparticles using new nanotechnology methods. Cellular uptake of miRNA was assessed by fluorescence microscope while MTT and qPCR assay were used to determine miRNA profile and the effect of CS-NP/miRNA on SKOV3 cells. Results: Results of profiling validated using quantitative realtime-polymerase chain reaction (PCR) found one of the most altered tumor suppressor miRNAs, miR-155-5p was downregulated 892.15-fold. According to bioinformatic analysis we identified the miRNA could recognize and regulate HIF1α expression. Transfection of mimics for miR-155-5p showed significantly increased miR-155-5p endogen SKOV3 expression level compared to the control group. We found differences after transfection mimics for miR-155-5p 31.5 and 63 nanoMolar. Increasing of miR-155-5p endogen lead to diminished SKOV3 viability (by 30%;

Barbara Bortot, 1 Maurizio Mongiat, 2 Erica Valencic, 3 Simeone Dal Monego, 4 Danilo Licastro, 4 Matteo Crosera, 5 Gianpiero Adami, 5 Enrico Rampazzo, 6 Giuseppe Ricci, 7, 8 Federico Romano, 7 Giovanni Maria Severini, 1 Stefania Biffi 7 1Department of Medical Genetics, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy; 2Department of Research and Diagnosis, Division of Molecular Oncology, Centro Di Riferimento Oncologico Di Aviano (CRO) IRCCS, Aviano, Italy; 3Department of Pediatrics, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy; 4ARGO Open Lab Platform for Genome Sequencing, AREA Science Park, Trieste, Italy; 5Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste, Italy; 6Department of Chemistry “G. Ciamician”, University of Bologna, Bologna, Italy; 7Department of Obstetrics and Gynecology, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy; 8Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, ItalyCorrespondence: Stefania Biffi Email stefania.biffi@burlo.trieste.itBackground: Platinum resistance is a major challenge in the management of ovarian cancer. Even low levels of acquired resistance at the cellular level lead to impaired response to cisplatin. In ovarian cancer intraperitoneal therapy, nanoparticle formulation can improve the cisplatin’s pharmacokinetics and safety profile.Purpose: This work aimed to investigate the chemo-sensitivity of ovarian cancer SKOV3 cells upon short-term (72h) single treatment of cisplatin and cisplatin-loaded biodegradable nanoparticles (Cis-NP). The aim was then to determine the therapeutic properties of Cis-NP in vivo using a SKOV3-luc cells’ xenograft model in mice.Methods: Cell cytotoxicity was assessed after the exposure of the cell culture to cisplatin or Cis-NP. The effect of treatments on EMT and CSC-like phenotype was studied by analyzing a panel of markers by flow cytometry. Intracellular platinum concentration was determined by inductively coupled plasma mass spectrometry (ICS-MS), and gene expression was evaluated by RNAseq analysis. The efficacy of intraperitoneal chemotherapy was evaluated in a SKOV3-luc cells’ xenograft model in mice, through a combination of bioluminescence imaging, histological, and immunohistochemical analyses.Results: We observed in vitro that short-term treatment of cisplatin has a critical role in determining the potential induction of chemoresistance, and a nanotechnology-based drug delivery system can modulate it. The RNAseq actg 3nalysis underlines a protective effect of nanoparticle system according to their ability to down-regulate several genes involved in chemoresistance, cell proliferation, and apoptosis. The highest intracellular platinum concentration obtained with Cis-NP treatment significantly improved the efficacy. Consistent with in vitro results, we found that Cis-NP treatment in vivo can significantly reduce tumor burden and aggressiveness compared to the free drug.Conclusion: Nanoparticle-mediated cisplatin delivery may serve as an intracellular depot impacting the cisplatin pharmacodynamic performance at cellular levels. These features may contribute to improving the drawbacks of conventional intraperitoneal therapy, and therefore will require further investigations in vivo.Keywords: cisplatin resistance, ovarian cancer, SKOV3, nanoparticle, epithelial-mesenchymal transition, Ca125, apoptosis

The present study aimed to explore the effect of ultrasound-stimulated microbubble cavitation (USMC) on drug concentration and therapeutic efficacy of oral gefitinib in treating subcutaneously transplanted SKOV3 ovarian cancer tumors in nude mice. The present study employed the VINNO70 ultrasonic diagnostic and treatment integrated machine for USMC therapy. Firstly, the mechanical index was set at 0.25, and the therapeutic efficacy of USMC treatment was assessed at intervals of 5, 10 and 20 min. Briefly, 72 nude mice were randomized into the following four groups (n=18/group): Control group, USMC 5 min group, USMC 10 min group and USMC 20 min group, and the therapeutic response to USMC treatment was evaluated by comparing pre-and post-intervention effects. Additionally, the combined therapeutic efficacy of USMC and gefitinib was investigated by randomly dividing 96 tumor-bearing mice into the following four groups (n=24/group): Control group, USMC group, gefitinib group and USMC + gefitinib group. Contrast-enhanced ultrasound, hematoxylin and eosin staining, western blotting, immunofluorescence staining, TUNEL staining, ELISA and liquid chromatography-mass spectrometry were performed in the present study. The results showed that USMC combined with gefitinib had the best treatment effect; the tumor inhibition rate was higher than that of gefitinib alone and the overall survival time was prolonged. In addition, the drug concentration in the tumor tissue obtained from the USMC + gefitinib group was revealed to be ~1.4 times higher than that detected in the group treated with gefitinib alone. The experimental results also confirmed that the strongest tumor inhibition rate and longest overall survival time was observed in the USMC + gefitinib group, followed by the gefitinib group and USMC group. STAT3 is an important signaling transducer and transcription factor, which, when phosphorylated, can lead to abnormal cell proliferation and malignant transformation. In addition, the upregulation of phosphorylated (p)-STAT3 is consider a reason for the poor efficacy of gefitinib in treating ovarian cancer. The present study revealed that ultrasound microbubble therapy could overcome this side effect. In conclusion, USMC improved the effects of oral gefitinib on subcutaneously transplanted SKOV3 ovarian cancer tumors in nude mice and increased drug penetration. In addition, USMC overcame the gefitinib-induced side effect of upregulated STAT3 phosphorylation and reduced the expression levels of p-STAT3 in the tumor., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Chen et al.)

Salvia triloba (S. triloba) is an herb inherently linked to traditional medicine systems in the Eastern Mediterranean region. There is minimal experimental evidence however, regarding the anticancer effects of S. triloba in both osteosarcoma and ovarian cancer. In this study, we investigated the effects of crude (macerated) S. triloba ethanol and acetone leaf extracts on viability, migratory ability, and the expression of genes regulating these activities in U2OS and SKOV3 cells using MTT assay, scratch-wound healing/trans-well migration assay, and RT-qPCR respectively. MTT assay results indicated that the acetone extract significantly reduced both U2OS and SKOV3 cell viability with half-maximal inhibitory concentrations (IC50) of 54.51 ± 1.10 µg/mL and 75.96 ± 1.0237 µg/mL respectively; these concentrations further displayed negligible hemolytic activity. The combination of acetone extract (19 µg/mL) and paclitaxel (0.787 µg/mL) displayed synergy and reduced SKOV3 cell viability by over 90%. Additionally, the trans-well migration assay illustrated that the acetone extract (IC50) inhibited both U2OS and SKOV3 cell migration by more than 50%. Moreover, S. triloba acetone extract significantly downregulated the steady-state mRNA expression of key genes involved in driving select cancer hallmarks. Four fractions were generated from the acetone extract by thin layer chromatography (TLC), and the obtained retention factors (Rf) (ranging from 0.2 to 0.8) suggested a mixture of high and moderately polar compounds whose bioactivities require further investigation. In addition, FTIR measurements of the extract revealed peaks corresponding to OH, aliphatic CH, and ester groups suggesting the presence of phenolic compounds, terpenes, and polysaccharides. Altogether, these results suggest that S. triloba possesses potential therapeutic compounds that inhibit cell proliferation and migration, and modulate several genes involved in osteosarcoma and ovarian carcinoma progression.

The current approach described the synthesis of a new series of indolylpyrrole derivatives through multicomponent reaction of α-cyano chalcones, appropriate aldehydes, and ammonium acetate in refluxed acetic acid. The chemical structures of the designed compounds were confirmed with spectroscopic data and elemental analysis and then tested for their in vitro cytotoxic activity by SRB assay method towards three cell lines involving human Prostate adenocarcinoma; metastatic cells (PC-3), human ovary adenocarcinoma (SKOV3) and human dukes' type B, colorectal adenocarcinoma (LS 174 T). Most significant activity provided with compounds 5c, 5h and, 5j against prostate cancer cells (PC-3) with IC50s of 3.30 ± 0.20, 3.60 ± 0.10, and 3.60 ± 0.90 µg/ml, respectively. In human ovarian carcinoma (SKOV3), the compounds 5a, and 5i have stronger cytotoxicity with IC50s of 1.20 ± 0.04, 1.90 ± 0.50 µg/ml, respectively than the standard doxorubicin (IC50 = 2.20 ± 0.02 µg/ml). On the other hand, only compound 5a has the ability to diminish the viability of LS174T cells in an active manner with IC50 2.80 ± 0.10 µg/ml. Consequently, this effort offers groundwork for additional examination of nominated indolylpyrroles as antiproliferative agents.

Fibrillar collagen is a one-dimensional biopolymer and is the most abundant structural protein in the extracellular matrix (ECM) of connective tissues. Due to the unique properties of carbon nanotubes (CNTs), considerable attention has been given to the application of CNTs in developing biocomposite materials for tissue engineering and drug delivery. When introduced to tissues, CNTs inevitably interact and integrate with collagen and impose a discernible effect on cells in the vicinity. The positive effect of the collagen-CNT (COL-CNT) matrix in tissue regeneration and the cytotoxicity of free CNTs have been investigated extensively. In this study, we aimed to examine the effect of COL-CNT on mediating the interaction between the matrix and SKOV3 ovarian cancer cells. We generated unidirectionally aligned collagen and COL-CNT nanofibrils, mimicking the structure and dimension of collagen fibrils in native tissues. AFM analysis revealed that the one-dimensional structure, high stiffness, and low adhesion of COL-CNT greatly facilitated the polarization of SKOV3 cells by regulating the β-1 integrin-mediated cell-matrix interaction, cytoskeleton rearrangement, and cell migration. Protein and gene level analyses implied that both collagen and COL-CNT matrices induced the epithelial-mesenchymal transition (EMT), and the COL-CNT matrix prompted a higher level of cell transformation. However, the induced cells expressed CD44 at a reduced level and MMP2 at an increased level, and they were responsive to the chemotherapy drug gemcitabine. The results suggested that the COL-CNT matrix induced the transdifferentiation of the epithelial cancer cells to mature, less aggressive, and less potent cells, which are inapt for tumor metastasis and chemoresistance. Thus, the presence of CNT in a collagen matrix is unlikely to cause an adverse effect on cancer patients if a controlled dose of CNT is used for drug delivery or tissue regeneration. [ABSTRACT FROM AUTHOR]

Khat (Catha edulis (Vahl) Endl.) is an evergreen flowering shrub used as a stimulant in many regions worldwide including East Africa, the Arabian Peninsula, Europe, and the United States. Chewing leaves of khat induces excitement and euphoria, which are primarily attributed to two major constituents, cathinone and cathine. Khat also contains other important constituents such as cathedulins. A considerable number of studies reported side effects induced by the khat extracts to both embryos and adults. These include teratogenicity and developmental retardation, oral cancer and ulcers, high blood pressure, and myocardial infarction. So far, little attention has been paid to the effects of khat extracts on the molecular signaling interactions. We aimed in this study to investigate this through evaluating the effects of khat extracts on SKOV3, a human ovarian adenocarcinoma cell line. We show, by in vitro assays, that khat induces several cellular defects including reduced cell size, cell membrane damage, and apoptosis. At high khat extract concentrations, the cell metabolic activity, cell cycle, and cellular proliferation were affected. RT-qPCR analysis showed an increase in the gene expression of the apoptotic marker BAX, the tumor suppressor p53, and the inflammatory cytokine IL-6. Protein expression analysis by immunostaining showed downregulation of β-catenin, E-cadherin, and Ki-67 and upregulation of FZD8 and SPRY2, suggesting that Wnt and FGF signaling were implicated. SwissTargetPrediction in silico analysis showed that khat constituents cathine, cathinone, catheduline K2, and catheduline E5 bind to family A G-protein-coupled receptor, cause many neurological diseases and disorders such as Alzheimer's, schizophrenia, depression, and anxiety, and induce many ovarian cancer-related diseases. The analysis also showed that important signaling pathways such as CREB, Wnt, FGF, IL-6, and ERK/MAPK, and that of the endometrial cancer, and cell cycle were implicated. Upstream regulators of cathine and cathinone were found to potentially target several molecules including interleukin-8, MMP2, PLAU, and micro-RNAs. In conclusion, khat induces significant cellular and molecular changes that could potentially cause a wide range of serious diseases and syndromes. Such an impact could have a heavy burden on the health care system in the countries where khat is consumed.

Purpose: To study the influence of curcumin on the survival of SKOV3 cells and the potential molecular mechanism of action. Methods: SKOV3 cell proliferation was measured using MTT assay. Gene expression levels were assayed using QRT-PCR assay, while protein expression was determined with western blotting. Results: Cell viability was reduced by curcumin at doses of 20, 40 and 80 µM (p < 0.05) in a dosebased fashion. Protein expression levels of Bax, caspase-3 and caspase-9 were upregulated by curcumin, while Bcl-2 protein level was downregulated (p < 0.05). Conclusion: These results demonstrate that curcumin inhibits cell proliferation by promoting the protein expressions of pro-apoptotic genes (Bax, caspase-3 and caspase-9) while suppressing Bcl-2 protein level. Therefore, curcumin might be a novel alternative therapy for ovarian cancer. [ABSTRACT FROM AUTHOR]

Targeted drug conjugates based on Affibody molecules fused to an albumin-binding domain (ABD) for half-life extension have demonstrated potent anti-tumor activity in preclinical therapeutic studies. Furthermore, optimization of their molecular design might increase the cytotoxic effect on tumors and minimize systemic toxicity. This study aimed to investigate the influence of length and composition of a linker between the human epidermal growth factor receptor 2 (HER2)-targeted affibody molecule (ZHER2:2891) and the ABD domain on functionality and biodistribution of affibody-drug conjugates containing a microtubulin inhibitor mertansin (mcDM1) (AffiDCs). Two conjugates, having a trimeric (S3G)3 linker or a trimeric (G3S)3 linker were produced, radiolabeled with 99mTc(CO)3, and compared side-by-side in vitro and in vivo with the original ZHER2:2891-G4S-ABD-mcDM1 conjugate having a monomeric G4S linker. Both conjugates with longer linkers had a decreased affinity to HER2 and mouse and human serum albumin in vitro, however, no differences in blood retention were observed in NMRI mice up to 24 h post injection. The use of both (S3G)3 and (G3S)3 linkers reduced liver uptake of AffiDCs by approximately 1.2-fold compared with the use of a G4S linker. This finding provides important insights into the molecular design for the development of targeted drug conjugates with reduced hepatic uptake.

Aim: This study aimed at evaluating the additional anti‐tumor effects of exogenous rVEGFR1 (sFlt1) on conventional chemotherapy in ovarian cancer cell lines. Methods: We utilized cells from two ovarian cancer cell lines, SKOV3 and HeyA8, and treated them with a combination of rVEGFR1 (sFlt1) and carboplatin as well as rVEGFR1 (sFlt1) alone. First, we evaluated cell survival after treatment by using cell counting and MTS assays. Next, we performed Ki67 staining for evaluating the inhibitory effects of the treatment on cell proliferation, and a lactate dehydrogenase (LDH) assay for evaluating cytotoxicity. Finally, to determine whether MAP kinase signaling is involved in this process, we performed western blot analysis of extracellular signal‐regulated kinase (ERK), phospho‐ERK, c‐jun n‐terminal kinase (JNK) and phospho‐JNK. Results: The cytotoxic and growth‐restriction effects were more pronounced in the group co‐administered with rVEGFR1 (sFlt1) and carboplatin than in cells treated with either rVEGFR1 (sFlt1) or carboplatin alone. Quantitative analysis of Ki67‐positive cells also showed a decreased proportion of Ki67‐positive cells in SKOV3 cells treated with a combination of exogeneous rVEGFR1 (sFlt1) and carboplatin compared to that in cells treated with either rVEGFR1 (sFlt1) or carboplatin alone. In the LDH assay, we also found significantly enhanced cell toxicity from the combination therapy. Finally, western blotting analysis showed that the MAPK signaling pathway was not affected by sFlt1 treatment. Conclusion: This study confirmed the additive effects of rVEGFR1 (sFlt1) combined with conventional chemotherapy for ovarian cancer growth in in vitro assays, thus suggesting the combination of rVEGFR1 (sFlt1) and carboplatin as a potential novel therapeutic option for ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Epithelial ovarian cancer (EOC) is the most common type of ovarian cancer and is the most lethal gynecologic malignancy. Cytokeratin 19 (CK19) is a small type I cytokeratin. The aim of this study is to explore the functional role of CK19 and its underlying mechanism in EOC. Methods: The expression levels of CK19 in EOC tissues were identified by Western blotting and RT-PCR assay. Transwell assay and CCK-8 proliferation assay were used to assess the invasion, migration and proliferation abilities of overexpressed or knockdown CK19 of ovarian cancer cells. We also detected the related genes of Wnt/β-catenin signal pathway, including β-catenin, TCF7, LEF1, c-MYC and cyclin D1 in the transfected ovarian cancer cells by Western blotting and RT-PCR assay. Results: The results demonstrated that CK19 was upregulated in EOC tissue. CK19 was verified to promote the invasion, proliferation and migration of ovarian cancer cells. Additionally, CK19 activates the Wnt/β-catenin signaling pathway by upregulated β-catenin, TCF7, LEF1, c-MYC and cyclin D1. Conclusions: In summary, this is the first study to investigate the role of CK19 in EOC. These findings provide a potential new therapeutic target for the clinical diagnosis and treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Nowadays, finding a novel, effective, biocompatible, and minimally invasive cancer treatment is of great importance. One of the most promising research fields is the development of biocompatible photothermal nanocarriers. PTT (photothermal therapy) with an NIR (near-infrared) wavelength range (700–2000 nm) would cause cell death by increasing intercellular and intracellular temperature. PTT could also be helpful to overcome drug resistance during cancer treatments. In this study, an amine derivative of phospholipid poly ethylene glycol (DSPE-PEG (5000) amine) was conjugated with SWCNTs (single-walled carbon nanotubes) to reduce their intrinsic toxicity. Toxicity studies were performed on lung, liver, and ovarian cancer cell lines that were reported to show some degree of drug resistance to cisplatin. Toxicity results suggested that DSPE-PEG (5000) amine SWCNTs might be biocompatible photothermal nanocarriers in PTT. Therefore, our next step was to investigate the effect of DSPE-PEG (5000) amine SWCNT concentration, cell treatment time, and laser fluence on the apoptosis/necrosis of SKOV3 cells post-NIR exposure by RSM and experimental design software. It was concluded that photothermal efficacy and total apoptosis would be dose-dependent in terms of DSPE-PEG (5000) amine SWCNT concentration and fluence. Optimal solutions which showed the highest apoptosis and lowest necrosis were then achieved.

Abstract Purpose One of the most common malignancies peculiar to female health with few symptoms, low response to therapy, difficult diagnosis, frequent relapse, and high mortality, is ovarian cancer. Thus, our experiment, using Human amniotic fluid mesenchymal stem cells (hAFMSCs) as a therapeutic tool, aims to find an efficient treatment approach for patients suffering from SKOV3 ovarian cancer. Material & Methods In this study, we obtained 5 ml amniotic fluid from 16–20 week pregnant women who underwent amniocentesis for routine prenatal diagnosis by karyotyping in Al‐Zahra Hospital of Tabriz University of Medical Sciences, Iran. Using trans wells in 24 wells plate, hAFMSCs were isolated from all samples, co‐cultured with SKOV3 ovarian cancer cell line, and characterized via flow cytometry and RT‐PCR. Human skin fibroblast cells (HSFCs) were isolated and used as a negative control. SKOV3 and HSFCs' viability after 5 days was evaluated by MTT assay. Cell cycle and apoptotic genes were analyzed by real‐time PCR. Results We successfully isolated and characterized hAFMSCs through it positivity for CD44 and CD90 specific mesenchymal stem cell markers and negativity for CD31 and CD45. Oct4 and NANOG were evaluated by RT‐PCR as pluripotency markers, and visualized on 2% gel electrophoresis. We established hAFMS cell lines after 5 days of co‐culturing the SKOV3 cells, viability was decreased; however, HSFCs did not show toxicity by MTT assay. The genes indicated upregulation and high expression by a real‐time PCR. Conclusions Our findings showed that hAFMSCs have natural tumor tropism, and can release soluble factors in a cell culture, which cause an efficient anticancer effect. Thus, we can use hAFMSCs for complete anticancer therapy on SKOV3 cell line at cell culture condition and possibly in vivo in the near future.

The anticancer activity of terretonin N (1) and butyrolactone I (2), obtained from the thermophilic fungus Aspergillus terreus TM8, was intensively studied against prostate adenocarcinoma (PC-3) and ovary adenocarcinoma (SKOV3) human cell lines. According to this study, both compounds showed potent cytotoxicity towards ovarian adenocarcinoma cells (SKOV3) with IC50 1.2 and 0.6 μg/mL, respectively. With respect to metastatic prostate cells (PC-3), the two compounds 1 and 2 showed a significantly promising cytotoxicity effect with IC50 of 7.4 and 4.5 μg/mL, respectively. The tested fungal metabolites showed higher rates of early and late apoptosis with little or no necrotic apoptotic pathway in all treated prostate adenocarcinoma (PC-3) and ovary adenocarcinoma (SKOV3) human cell lines, respectively. The results reported in this study confirmed the promising biological properties of terretonin N (1) and butyrolactone I (2) as anticancer agents via the induction of cellular apoptosis. However, further studies are needed to elucidate the molecular mechanism by which cellular apoptosis is induced in cancer cells.

Oxidative stress is the major cause of many health conditions, and regular consumption of antioxidants helped to encounter and prevent such oxidative stress-related diseases. Due to safety concerns over long-term uses of synthetic antioxidants, natural antioxidants are more preferred. The purpose of this study is to investigate the antioxidant and anticancer activities of Jussiaea repens L., a wild edible flora found in Manipur, India. The antioxidant activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), Ferric reducing antioxidant power (FRAP) assay and DNA-nicking assay. The anticancer activity was tested using five cancer lines viz., SKOV3 cells (ovarian), HeLa (cervical), MDA-MB-231 (breast), PANC-1 (pancreatic), and PC3 (prostate). The toxicity, developmental effect, antiproliferative activity was further tested using zebrafish embryos. The methanolic plant extract had higher polyphenol content than flavonoids. The in vitro study demonstrated a promising antioxidant capacity and DNA protection ability of this plant. The extract also showed cytotoxic activity against SKOV3, HeLa, MDA-MB-23, and PANC-1 cancer cell lines. The in vivo studies on zebrafish embryos demonstrated the extract’s ability to suppress the developmental process and elicited more cytotoxicity to cancer cells than developing zebrafish embryos. Moreover, the in vivo studies on zebrafish embryos also indicated the antiproliferative activity of J. repens L. extract.

Circulating tumor cell (CTC) test is currently used as a biomarker in cancer treatment. Unfortunately, the poor reproducibility and limited sensitivity with the CTC detection have limited its potential impact on clinical application. A reliable automated CTC detection system is therefore needed. We have designed an automated microfluidic chip-based CTC detection system and hypothesize this novel system can reliably detect CTC from clinical specimens. SKOV3 ovarian cancer cell line was used first to test the reliability of our system. Ten healthy volunteers, 5 patients with benign ovarian tumors, and 8 patients with epithelial ovarian cancer (EOC) were recruited to validate the CTC capturing efficacy in the peripheral blood. The capture rates for spiking test in SKOV3 cells were 48.3% and 89.6% by using anti-EpCAM antibody alone and a combination of anti-EpCAM antibody and anti-N-cadherin antibody, respectively. The system was sensitive to detection of low cell count and showed a linear relationship with the cell counts in our test range. The sensitivity and specificity were 62.5% and 100% when CTC was used as a biomarker for EOC. Our results demonstrated that this automatic CTC platform has a high capture rate and is feasible for detection of CTCs in EOC.