Human Ovarian Carcinoma Cell Line Research Articles

Establishment of a human ovarian clear cell carcinoma cell line mutant in PIK3CB but not PIK3CA.

A human ovarian clear cell carcinoma cell line was established from a 46-year-old Japanese woman. That line, designated MTC-22, has proliferated continuously for over 6months in conventional RPMI 1640 medium supplemented with 10% foetal bovine serum and has been passaged over 50 times. MTC-22 doubling-time is ~ 18h, which is much shorter than most ovarian clear cell carcinoma lines reported to date. Morphologically, MTC-22 cells exhibit polygonal shapes and proliferate to form a monolayer in a jigsaw puzzle-like arrangement without contact inhibition. Ultrastructurally, cells exhibit numerous intracytoplasmic glycogen granules and well-developed mitochondria. G-band karyotype analysis indicated that cells have a complex karyotype close to tetraploid. We observed that the expression pattern of a series of ovarian carcinoma-related molecules in MTC-22 cells was identical to that seen in the patient's tumour tissue. Notably, MTC-22 cells, and the patient's carcinoma tissue, expressed low-sulphated keratan sulphate recognised by R-10G and 294-1B1 monoclonal antibodies, a hallmark of non-mucinous ovarian carcinoma, and particularly of clear cell ovarian carcinoma. Moreover, characteristic point mutations-one in ARID1A, which encodes the AT-rich interaction domain containing protein 1A, and the other in PIK3CB, which encodes the catalytic subunit of phosphoinositide 3-kinase-were seen in the patient's tumour tissue and retained in MTC-22 cells. Collectively, these findings indicate that MTC-22 cells could serve as a valuable tool for investigating the pathophysiology of ovarian clear cell carcinoma, particularly that harbouring PIK3CB mutations, and for developing and validating new diagnostic and therapeutic approaches to this life-threatening malignancy.

Structural Elucidation and Prognostic Relevance of 297-11A-Sulfated Glycans in Ovarian Carcinoma

Ovarian carcinoma is usually diagnosed at an advanced stage with peritoneal dissemination and/or lymph node metastasis, and the prognosis for such advanced carcinoma is very poor. Therefore, new biomarkers to predict patient prognosis are needed. Miyamoto et al. previously showed that keratan sulfate (KS) detected by the 5D4 monoclonal antibody was expressed in ovarian carcinoma. However, the detailed structure of such KS was not determined, and the biological significance of this finding remained to be clarified. We previously generated the 297-11A monoclonal antibody, which recognizes galactose (Gal)-6-O-sulfated N-acetyllactosamine (LacNAc) located at the nonreducing terminus. Because the 297-11A epitope overlaps with that of 5D4, here we chose to use the 297-11A antibody as a tool to analyze KS and related structures. We conducted immunohistochemical analysis of 98 ovarian carcinoma cases with 297-11A antibody combined with a series of glycosidases and performed mass spectrometry analysis of the human serous ovarian carcinoma cell line OVCAR-3 to deduce the glycan structure of 297-11A-sulfated glycans. We also performed western blot analysis to assess a potential association of 297-11A-sulfated glycans with the mucin core protein mucin 16 (MUC16; also known as cancer antigen 125 (CA125)). Finally, we examined the relationship between 297-11A expression and patient prognosis. Consequently, 297-11A-sulfated glycans were primarily expressed in serous and endometrioid carcinomas and poorly expressed in mucinous and clear cell carcinomas. We reveal that structurally, 297-11A-sulfated glycans expressed in ovarian carcinoma are O-glycans carrying partially sialylated, Gal-6-O-sulfated LacNAc and that these glycans are likely displayed on MUC16 mucin core proteins. Of clinical importance is that expression of 297-11A-sulfated glycans correlated with shorter progression-free survival in patients. Thus, 297-11A-sulfated glycans may serve as a predictor of ovarian carcinoma recurrence.

A PILOT IN VITRO STUDY ON THE EFFECT OF BLUE HONEYSUCKLE EXTRACT ON HUMAN NON-CANCEROUS AND CANCEROUS OVARIAN CELLS

Honeysuckle (Lonicera caerulea L.) is utilized in Chinese, Japanese, and Russian folk medicines for centuries. The berries referred to as blue honeysuckle are recently gaining popularity in central and southern Europe due to remarkable therapeutic potential and widespread use as an ingredient in dietary supplements. The primary objective of this investigation was to examine the impact of blue honeysuckle extract on human ovarian cells – both non-cancerous HGL5 (immortalized human ovarian granulosa cell line) and cancerous OVCAR-3 (human ovarian carcinoma cell line). Cell viability, secretion of steroid hormones (17ß-estradiol and progesterone), human transforming growth factor-β2 (TGFβ-2) and its receptor (TGFBR2), and the level of apoptosis-inducing factor (AIF) were examined in ovarian granulosa cells HGL5, and the same parameters (excepting the steroid hormones) were assessed in ovarian epithelial cancer cells OVCAR-3. Blue honeysuckle ethanolic extract was applied to cells for 24 hours. AlamarBlueTM assay was used to assess cell viability, whereas secretion of steroid hormones was evaluated by ELISA. ELISA was also used to assess the levels of TGF-β2, its receptor TGFBR2 and AIF in HGL5 and OVCAR-3 cell lysates. Based on a range of doses ranging from 5 – 100 μg/mL, the extract from blue honeysuckle had no adverse effects on the viability of human ovarian cells. Futuremore, it did not affect their secretory activity – be it the release of steroid hormones or that of growth factor TGF-β2 and its receptor TGFBR2, nor did induce apoptosis (as revealed by the AIF). The present pilot study for the first time reports the effect of blue honeysuckle extract on ovarian cell models using both non-cancerous cells HGL5 and cancerous OVCAR-3 cells. These findings provide initial insights into the safety and potential utility of blue honeysuckle extract, warranting further investigation into its therapeutic applications. In further research, it is possible to examine a longer exposure time to see if it affects the cells.

Abstract IA014: From targeted phenotypic screen to NXP800: A clinical stage activator of the integrated stress response for the treatment of ARID1A-mutated ovarian carcinoma

Abstract IA014: From targeted phenotypic screen to NXP800: A clinical stage activator of the integrated stress response for the treatment of ARID1A-mutated ovarian carcinoma

Novel ternary Pd(II) complexes as potent anticancer drugs for ovarian carcinoma treatment

A novel straightforward method has been introduced to synthesize two new water soluble Pd complexes, [Pd(phd)(AA)]NO3, (phd = 1,10-phenanthroline-5,6-dione; 1, AA = L-isoleucine and 2, AA = L-leucine) using water as a green solvent. Complexes 1 and 2 have been characterized by elemental analysis, FT-IR, 1H NMR spectroscopy and mass spectrometry. A theoretical study of these complexes was conducted using ADME, DFT, and molecular docking. ADME data revealed these complexes as potentially anti-cancer drugs. Fluorescence, UV–Vis, and CD spectroscopy were applied to study the mechanism of DNA interaction. As a result of the fluorescence data, both complexes statically quenched DNA. Based on thermodynamic parameters, Pd(II) complexes and DNA interact via an electrostatic approach and groove binding. CD spectra indicated that both complexes exhibit a slight blue shift with a decrease in intensity across all bands. The experimental data were in agreement with DFT calculations and docking studies. In sum, the mode of binding with DNA intracellular structure is via groove binding and electrostatic interactions. Cytotoxic screening of these compounds carried out against the human ovarian carcinoma cell line A2780SP and cisplatin-resistant variant A2780CP revealed that both complexes showed significantly higher anticancer activity against A2780CP cancer cell line compared to cisplatin. Moreover, all theoretical and experimental data show that complex 2 is more active than complex 1.

Characterization of global research trends and prospects on platinum-resistant ovarian cancer: a bibliometric analysis.

In the last decades, growing attention has been focused on identifying effective therapeutic strategies in the orphan clinical setting of women with platinum-resistant ovarian cancer (PROC), generating thousands of original articles. However, the literature involving bibliometric analysis of PROC has not been published yet. This study hopes to gain a better understanding of the hot spots and trends in PROC by conducting a bibliometric analysis, as well as identify potential new research directions. We searched the Web of Science Core Collection (WOSCC) for PROC-related articles published between 1990 and 2022. CiteSpace 6.1.R2 and VOS viewer 1.6.18.0 were primarily utilized to evaluate the contribution and co-occurrence relationships of various countries and regions, institutes, and journals and to identify research hotspots and promising future trends in this research field. A total of 3,462 Web of Science publications were retrieved that were published in 671 academic journals by 1135 authors from 844 organizations in 75 countries and regions. The United States was the leading contributor in this field, and the University of Texas MD Anderson Cancer Center was the most productive institution. Gynecologic Oncology was the most productive journal, while the Journal of Clinical Oncology was the most cited and influential. Co-citation cluster labels revealed the characteristics of seven major clusters, including synthetic lethality, salvage treatment, human ovarian-carcinoma cell line, PARP inhibitor resistance, antitumor complexes, folate receptor, and targeting platinum-resistant disease. Keywords and references burst detection indicated that biomarkers, genetic and phenotypic changes, immunotherapy, and targeted therapy were the most recent and most significant aspects of PROC research. This study conducted a comprehensive review of PROC research using bibliometric and visual techniques. Understanding the immunological landscape of PROC and identifying the population that can benefit from immunotherapy, especially in combination with other therapeutic options (such as chemotherapy and targeted therapy), will continue to be the focal point of research.

Tris(aminomethyl)phosphines and Their Copper(I) (Pseudo)halide Complexes with Aromatic Diimines-A Critical Retrospection.

Metal complexes feature a wide range of available geometries, diversified lability, controllable hydrolytic stability, and easily available rich redox activity. These characteristics, combined with the specific properties of coordinated organic molecules, result in many different mechanisms of biological action, making each of the myriads of the classes of metal coordination compounds unique. This focused review presents combined and systematized results of the studies of a group of copper(I) (pseudo)halide complexes with aromatic diimines and tris(aminomethyl)phosphines of a general formula [CuX(NN)PR3], where X = I- or NCS-, NN = 2,2'-bipyridyl, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline or 2,2'-biquinoline, and PR3 = air-stable tris(aminomethyl)phosphines. The structural and electronic properties of the phosphine ligands and luminescent complexes are discussed. The complexes with 2,9-dimethyl-1,10-phenanthroline, apart from being air- and water-stable, exhibit a very high in vitro antimicrobial activity against the Staphylococcus aureus and Candida albicans. Moreover, some of these complexes also show a strong in vitro antitumor activity against human ovarian carcinoma cell lines: MDAH 2774 and SCOV 3, CT26 (mouse colon carcinoma), and A549 (human lung adenocarcinoma) cell lines. The tested complexes are moderately able to induce DNA lesions through free radical processes, however the trends do not reflect observed differences in biological activity.

Abstract 6020: The role of TP53 mutation status in the response to DNA methyltransferase inhibitor treatment

Abstract The purpose of this study was to understand the effect of p53 mutation status in ovarian cancer cells on the expression of repetitive elements (REs) following epigenetic treatment. High-grade serous ovarian carcinoma is the most aggressive subtype of ovarian cancer and the 5 year survival rate has remained unchanged for over two decades. Over 90% of high-grade serous ovarian carcinoma (OC) patients have a mutation in the TP53 gene, which encodes the p53 protein. P53 is a transcription factor primarily involved in maintaining genome integrity, but it can also regulate the expression of REs in the genome. REs account for more than half of the genome and these repetitive genomic elements are epigenetically silenced in healthy cells to prevent genome instability. The expression of some REs, such as long interspersed nuclear elements and endogenous retroviruses, are upregulated in human OC patients and cell lines. The mechanism by which p53 regulates expression of REs is not well-understood; the literature documents some instances of p53 activating RE transcription and others of p53 repressing RE transcription, depending on the target elements. We have previously shown that RE expression can be induced by treating OC cells with low doses of DNA methyltransferase inhibitors (DNMTis). Recently, we showed that OC cell lines with mutant p53 have higher baseline expression of REs compared to wild type (WT) cell lines. Treatment of TP53 mutant OC cell lines with DNMTis had a muted effect on RE expression compared to treatment of WT OC cell lines. To explore the relationship between TP53 mutation status and RE expression after DNMTi treatment, OC cell lines with different p53 mutation statuses were treated with 500 nM of the DNMTi 5-azacytidine. We then analyzed the expression of several REs via RT-qPCR and western blot. We hypothesized that TP53 mutant cell lines would have lower DNMTi upregulation of REs than TP53 WT cell lines. While at the RNA level RE expression was variable, at the protein level, we found that DNMTi treatment increased protein levels of several REs in TP53 WT and mutant, but not null, OC cell lines. Future work will examine the feasibility of utilizing these RE proteins as immunotherapy targets in OC. Citation Format: Khadra K. Omar, Erin E. Grundy, Olivia Cox, Melissa Hadley, Katherine B. Chiappinelli. The role of TP53 mutation status in the response to DNA methyltransferase inhibitor treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6020.

Proteomic Study on Multi-Organ Metastases of Human Ovarian Clear Cell Carcinoma Cell Line in a Xenograft Mouse Model Based on a Novel Sequence-Specific Analysis Strategy.

To investigate the gene regulation of tumor cells in the process of different organ metastasis on a xenograft mouse model and screen the genes involved in the organ-target metastasis of tumor cells. A multi-organ metastasis model was constructed with a human ovarian clear cell carcinoma cell line (ES-2) based on a severe immunodeficiency mouse strain (NCG). Differentially expressed tumor proteins among multi-organ metastases were successfully characterized by microliter liquid chromatography-high-resolution mass spectrometry, sequence-specific data analysis and multivariate statistical data analysis. Liver metastases were selected as typical for subsequent bioinformatic analysis. Selected liver metastasis-specific genes in ES-2 cells were validated by sequence-specific quantitation including high resolution-multiple reaction monitoring quantification at protein level and quantitative real-time polymerase chain reaction at mRNA level. From the mass spectrometry data, a total of 4503 human proteins were identified using the sequence-specific data analysis strategy. Of them, 158 proteins were selected as specifically regulated genes in liver metastases for subsequent bioinformatics studies. Based on Ingenuity Pathway Analysis (IPA) pathway analysis and sequence-specific quantitation, Ferritin light chain (FTL), lactate dehydrogenase A (LDHA) and long-chain-fatty-acid-CoA ligase 1 (ACSL1) were finally validated as specifically upregulated proteins in liver metastases. Our work provides a new approach to analyze gene regulation in tumor metastasis in xenograft mouse model. In presence of a large number of mouse protein interference, we validated the up-regulation of human ACSL1, FTL and LDHA in ES-2 liver metastases, which reflects the adaptive regulation of tumor cells to the liver microenvironment through metabolic reprogramming.

Catechin, rutin and quercetin in Quercus mongolica Fisch leaves exert inhibitory effects on multiple cancer cells.

We aimed to identify anti-tumor agents in Quercus mongolica Fisch (QMF). Bioactive compounds in QMF leaves, which were extracted using ethanol as a co-solvent. Five point zero six grams of flavonoids were obtained from 100 g of QMF leaves. Catechin (18.4%), rutin (6.3%), ellagic acid (34.9%), quercetin (5.1%) and kaempferol (20.6%) are the main ingredients of the extracts and were further purified by HPLC. CCK-8 cell proliferation assay showed that catechin and ellagic acid exerted strong inhibitory effects on the proliferation of all cancer cells with lower IC50 values against MCF-7 human breast cancer cell lines, SMMC-7721 human hepatocellular carcinoma cells, HeLa human cervical carcinoma cell lines and SKOV3 human ovarian carcinoma cell lines (p < .05). Catechin, rutin and quercetin induced a higher rate of apoptosis and inhibited all cancer cell proliferation by inducing the G0/G1 phase and G2/M phase arrest (p < .05). However, ellagic acid induced tumor cell death, not through apoptosis and there may be other molecular mechanisms. High levels of catechin and ellagic acid in QMF can be developed as potential drugs to treat different types of cancer cells. PRACTICAL APPLICATIONS: Quercus species have been widely studied because of their antioxidant, anti-inflammatory, antimicrobial, and anti-tumor properties. Bioactive compounds in the leaves of Quercus mongolica Fisch have high levels of catechin and ellagic acid, which exert significant inhibitory properties on the proliferation of various types of cancer cells. Therefore, the bioactive compounds may be potential natural drugs in the prevention of cancer development and progression.

Enhanced ZNF521 expression induces an aggressive phenotype in human ovarian carcinoma cell lines.

Epithelial ovarian carcinoma (EOC) is the most lethal gynecological tumor, that almost inevitably relapses and develops chemo-resistance. A better understanding of molecular events underlying the biological behavior of this tumor, as well as identification of new biomarkers and therapeutic targets are the prerequisite to improve its clinical management. ZNF521 gene amplifications are present in >6% of OCs and its overexpression is associated with poor prognosis, suggesting that it may play an important role in OC. Increased ZNF521 expression resulted in an enhancement of OC HeyA8 and ES-2 cell growth and motility. Analysis of RNA isolated from transduced cells by RNA-Seq and qRT-PCR revealed that several genes involved in growth, proliferation, migration and tumor invasiveness are differentially expressed following increased ZNF521 expression. The data illustrate a novel biological role of ZNF521 in OC that, thanks to the early and easy detection by RNA-Seq, can be used as biomarker for identification and treatment of OC patients.

The activation of M2 muscarinic receptor inhibits cell growth and survival in human epithelial ovarian carcinoma.

Ovarian cancer is the fifth leading cause of cancer-related deaths in females. Many ovarian tumor cell lines express muscarinic receptors (mAChRs), and their expression is correlated with reduced survival of patients. We have characterized the expression of mAChRs in two human ovarian carcinoma cell lines (SKOV-3, TOV-21G) and two immortalized ovarian surface epithelium cell lines (iOSE-120, iOSE-398). Among the five subtypes of mAChRs (M1-M5 receptors), we focused our attention on the M2 receptor, which is involved in the inhibition of tumor cell proliferation. Western blot analysis and real-time PCR analyses indicated that the levels of M2 are statistically downregulated in cancer cells. Therefore, we investigated the effect of arecaidine propargyl ester hydrobromide (APE), a preferential M2 agonist, on cell growth and survival. APE treatment decreased cell number in a dose and time-dependent manner by decreasing cell proliferation and increasing cell death. FACS and immunocytochemistry analysis have also demonstrated the ability of APE to accumulate the cells in G2/M phase of the cell cycle and to increase the percentage of abnormal mitosis. The higher level of M2 receptors in the iOSE cells rendered these cells more sensitive to APE treatment than cancer cells. The data here reported suggest that M2 has a negative role in cell growth/survival of ovarian cell lines, and its downregulation may favor tumor progression.

Nisin induces apoptosis in cervical cancer cells via reactive oxygen species generation and mitochondrial membrane potential changes.

Nisin, an antimicrobial peptide produced by Lactococcus lactis, is widely used as a safe food preservative and has recently attracted the attention of researchers as a potential anticancer agent. The cytotoxicity of nisin against human cervical cancer cell lines (HeLa), human ovarian carcinoma cell lines (OVCAR-3 and SK-OV-3), and human umbilical vein endothelial cells (HUVECs) was evaluated using an MTT assay. The apoptotic effect of nisin was identified by Annexin-V/propidium iodide assay, which was further confirmed by western blotting analysis, mitochondrial membrane potential (ΔΨm) analysis, and reactive oxygen species (ROS) assay. The MTT assay showed concentration-dependent cytotoxicity of nisin towards cancer cell lines, with IC50 values of 11.5-23 µM, but less toxicity against normal endothelial cells. Furthermore, the treatment of cervical cancer cells with 12 µM nisin significantly (P < 0.05) increased the Bax/Bcl-2 ratio (4.9 fold), reduced ΔΨm (70%), and elevated ROS levels (1.7 fold). These findings indicate that nisin may have anticancer and apoptogenic activities through mitochondrial dysfunction and oxidative stress damage in cervical cancer cells.

Nickel Nanoparticles Originated from Cressa Leaf Extract in the Preparation of a Novel Melem@Ni-HPA Photocatalyst for the Synthesis of Some Chromenes and a Preliminary MTT Assay on the Anticancer Activity of the Nanocomposite

Organic photochemical synthesis with visible-light has attracted much attention in recent years by academia and industrial societies due to green features of this strategy. The present study mainly focuses on the preparation of Melem@Ni-HPA nanocomposite and application of this magnetic material as an efficient photocatalyst in the fabrication of different chromenes under simple and practical conditions. The target cromenes are prepared via condensation of coumarin, aromatic aldehyde and dimedone in an open-air condition by the help of a commercial green laser in acetonitrile. Then, the structural and morphological characteristics of this new nanophotocatalyst was evaluated by routine techniques such as X-Ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FT-IR), dynamic light scattering (DRS), scanning electron microscope (SEM), energy dispersive X-ray spectroscopy (EDS) and vibrating-sample magnetometry (VSM). Notable advantages of this new methodology include short reaction time, cost-effectiveness, facile separation of the catalyst by a magnet, excellent performance, and acceptable atom economy. A number of contributing experimental variables are also fully attended to unravel the broadness and generality of this method. In addition, progression of the reaction seems to proceed through a radical mechanism and suggest that reactive species like •O2 – and OH• along with h+ are implicated in the photocatalytic mechanism. Reusability and stability experiments also confirmed acceptable reproducibility of the nanophotocatalyst in at least five runs. Finally, the in-vitro cellular cytotoxicity of melem@Ni-HPA nanocomposite was tested against SKOV3 human ovarian carcinoma cell line via a preliminary MTT assay. The reduction in cell viability confirmed cytotoxicity of this nanomaterial on the selected cancer cell line.

Peritoneal Modulators of Endometriosis-Associated Ovarian Cancer.

Ovarian cancer is the 4th largest cause of cancer death in women. Approximately 10–15% of women of childbearing age suffer from endometriosis. Endometriosis is defined by the growth and presence of endometrial tissue (lesions) outside of the uterus. The women with endometriosis also have an increased presence of peritoneal fluid (PF) that comprises of inflammatory cells, growth factors, cytokines/chemokines, etc. Epidemiological studies have shown that >3% of women with endometriosis develop ovarian cancer (low-grade serous or endometrioid types). Our hypothesis is that the PF from women with endometriosis induces transformative changes in the ovarian cells, leading to ovarian cancer development. PF from women with and without endometriosis was collected after IRB approval and patient consent. IOSE (human normal ovarian epithelial cells) and TOV-21G cells (human ovarian clear cell carcinoma cell line) were treated with various volumes of PF (no endometriosis or endometriosis) for 48 or 96 h and proliferation measured. Expression levels of epigenetic regulators and FoxP3, an inflammatory tumor suppressor, were determined. A Human Cancer Inflammation and Immunity Crosstalk RT2 Profiler PCR array was used to measure changes in cancer related genes in treated cells. Results showed increased growth of TOV-21G cells treated with PF from women with endometriosis versus without endometriosis and compared to IOSE cells. Endo PF treatment induced EZH2, H3K27me3, and FoxP3. The RT2 PCR array of TOV-21G cells treated with endo PF showed upregulation of various inflammatory genes (TLRs, Myd88, etc.). These studies indicate that PF from women with endometriosis can both proliferate and transform ovarian cells and hence this microenvironment plays a major mechanistic role in the progression of endometriosis to ovarian cancer.

Gold(I) Complexes with P-Donor Ligands and Their Biological Evaluation

Gold(I) complexes with phosphine ligands—[Au(TrippyPhos)Cl] (1) (TrippyPhos = 1-[2-[bis(tert-butyl)phosphino]phenyl]-3,5-diphenyl-1H-pyrazole), [Au(BippyPhos)Cl]0.5CH2Cl2 (2) (BippyPhos = 5-(di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole), and [Au(meCgPPh)Cl] (3) (meCgPPh = 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane—were investigated as types of bioactive gold metallodrugs. Complexes (1)–(3) were characterized using IR, 1H, 13C, 31P NMR spectroscopy, elemental analysis and mass spectrometry (FAB-MS). Complexes of (1) and (2) exhibited substantial in vitro cytotoxicity (IC50 = 0.5–7.0 μM) against both the cisplatin-sensitive and -resistant variants of the A2780 human ovarian carcinoma cell line, as well as against the A549 human lung carcinoma, K562 chronic myelogenous leukemia, and HeLa (human cervix carcinoma) cells. However, among the compounds studied, complex (2) showed the most promising biological properties: the highest stability in biologically relevant media, selectivity towards cancer cells over the non-cancer cells (HUVEC, human umbilical vein endothelial cells), and the highest inhibitory effect on cytosolic NADPH-dependent reductases in A2780 and A2780cis cells among the gold complexes under analysis.

A Possible Inhibitory Role of Sialic Acid on MUC1 in Peritoneal Dissemination of Clear Cell-Type Ovarian Cancer Cells.

The role of sialic acids on MUC1 in peritoneal dissemination of ovarian cancer cells was investigated. A human ovarian carcinoma cell line, ES-2, was transfected with full-length MUC1 containing 22 or 42 tandem repeats. These transfectants were less adherent to monolayers of patient-derived mesothelial cells than ES-2/mock transfectants. When these cells were inoculated into the abdominal cavity of female nude mice, mice that had received the transfectants showed better survival. When the transfectants were mixed with sialidase and injected, the survival was poorer, whereas when they were mixed with N-acetyl-2,3-dehydro-2-deoxyneuraminic acid, a sialidase inhibitor, the survival was significantly prolonged. These behaviors, concerned with peritoneal implantation and dissemination observed in vitro and in vivo, were dependent on the expression of MUC1. Therefore, sialic acid linked to MUC1 in the form, at least in part, of sialyl-T, as shown to be recognized by monoclonal antibody MY.1E12, is responsible for the suppression of adhesion of these cells to mesothelial cells and the suppression of peritoneal implantation and dissemination.

Quinazolin-4(3H)-one based potential multiple tyrosine kinase inhibitors with excellent cytotoxicity

A series of quinazolin-4(3H)-one derivatives were synthesised and evaluated for their cytotoxicity against human Caucasian breast adenocarcinoma (MCF-7) and human ovarian carcinoma (A2780) cell lines. Cytotoxicity of the most tested compounds was 2- to 30-fold more than the positive control lapatinib (IC50 of 2j = 3.79 ± 0.96; 3j = 0.20 ± 0.02; and lapatinib = 5.9 ± 0.74) against MCF7 cell lines except two compounds (IC50 of 2 b = 15.72 ± 0.07 and 2e = 14.88 ± 0.99). On the other hand, cytotoxicity was 4 − 87 folds (IC50 of 3a = 3.00 ± 1.20; 3 g = 0.14 ± 0.03) more the positive control lapatinib (IC50 = 12.11 ± 1.03) against A2780 cell lines except compound 2e (IC50 = 16.43 ± 1.80). Among the synthesised quinazolin-4(3H)-one derivatives, potent cytotoxic 2f-j and 3f-j were investigated for molecular mechanism of action. Inhibitory activities of the compounds were tested against multiple tyrosine protein kinases (CDK2, HER2, EGFR and VEGFR2) enzymes. As expected, all the quinazolin-4(3H)-one derivatives were showed comparable inhibitory activity against those kinases tested, especially, compound 2i and 3i showed potent inhibitory activity against CDK2, HER2, EGFR tyrosine kinases. Therefore, molecular docking analysis for quinazolin-4(3H)-one derivatives 2i and 3i were performed, and it was revealed that compounds 2i and 3i act as ATP non-competitive type-II inhibitor against CDK2 kinase enzymes and ATP competitive type-I inhibitor against EGFR kinase enzymes. However, in case of HER2, compounds 2i act as ATP non-competitive type-II inhibitor and 3i act as ATP competitive type-I inhibitor. Docking results of known inhibitors were compared with synthesised compounds and found synthesised 2i and 3i are superior than the known inhibitors in case of interactions. In addition, in silico drug likeness properties of quinazolin-4(3H)-one derivatives showed better predicted ADME values than lapatinib.

Elevated expression of Tweety homologue 3 predicts poor clinical outcomes in ovarian cancer.

Objective: To define the alteration of tweety homolog (TTYH) expression in patients with ovarian carcinoma (OC) and its correlation to prognosis.Methods: Kaplan-Meier (KM) plotter was used to evaluate the association between TTYHs expression and clinical outcomes of OC patients. The distribution of 20-year overall survival (OS) and progression-free survival (PFS) was estimated using KM survival plots. The mRNA expression of TTYHs in OC and normal ovarian tissues was confirmed by the Oncomine database. Then, using immunohistochemistry assay, the expression of TTYH1 and TTYH3 proteins in serous OC and normal ovarian tissues was detected. In addition, the protein and mRNA levels of TTYH1 and TTYH3 in human OC cell lines ES-2, A2780 and SKOV3 and normal ovarian epithelial cell lines IOSE80 were assessed by western blotting and real-time quantitative polymerase chain reaction (qRT-PCR).Results: TTYH1 possessed meaningful significance in predicting better prognosis in the serous, advanced stage, and well-differentiated OC patients, while TTYH3 expression predicted worse prognosis in serous, late-stage, and poorly differentiated OC patients. High expression of TTYH1 displayed an association with favorable PFS in OC patients with TP53 mutation. However, enhanced TTYH3 was related to an adverse clinical outcome in TP53-mutated OC patients. In addition, TTYH1 was related to a better clinical outcome in OC patients with platinums-based chemotherapy, but only indicated improved overall survival in OC patients who received taxol or platin + taxol chemotherapy. The up-regulated expression of TTYH3 predicted worse survival in OC patients receiving platin, taxol, or platin + taxol chemotherapy regimen. The levels of TTYH3 mRNA and protein were higher in OC cells and tissues when compared to normal ovarian cells and tissues.Conclusions: TTYH3 was a potential predictor for poor clinical outcome in OC patients, particularly in patients with serous, late-stage, poorly differentiated, TP53-mutation or the patients treated with chemotherapy regimens (platin, taxol, or platin + taxol).

Withdrawal: ETS-1 protein regulates vascular endothelial growth factor-induced matrix metalloproteinase-9 and matrix metalloproteinase-13 expression in human ovarian carcinoma cell line SKOV-3.

VOLUME 287 (2012) PAGES 15001–15015 The article has been withdrawn by the authors. The authors were made aware that the panel corresponding to lanes 3 and 4 of the total Akt immunoblot in Fig. 3A was reused as a GAPDH panel in Fig. 6B. In addition, the panel corresponding to the GAPDH immunoblot in Fig. 3A was inappropriately manipulated to reduce background noise. The authors responded that all the experiments were executed appropriately, and the data obtained at that time or by subsequent experiments support the original conclusion of the paper. Furthermore, the authors state that these issues do not affect the accuracy of the overall results or the conclusions of the scientific work (i.e. the conclusion of Fig. 6B has been shown in another way in Fig. 6A, and that of Fig. 3A has been shown in Fig. 9B in the same article). However, to set precedence for upcoming research work and be consistent with JBC editorial practice, the authors wish to withdraw this article.