Newly Developed Dual Topoisomerase Inhibitor P8-D6 is Highly Active in Ovarian Cancer

Background: Ovarian cancer (OvCa) constitutes a rare and highly aggressive malignancy and is one of the most lethal of all gynaecologic neoplasms. Due to chemotherapy resistance and treatment limitations because of side effects, OvCa is still not sufficiently treatable. Hence, new drugs for OvCa therapy such as P8-D6 with promising antitumour properties have a high clinical need. The benzo[c]phenanthridine P8-D6 is an effective inductor of apoptosis by acting as a dual topoisomerase I/II inhibitor. Methods: In the present study, the effectiveness of P8-D6 on OvCa was investigated in vitro. In various OvCa cell lines and ex vivo primary cells, the apoptosis induction compared to standard therapeutic agents was determined in 2D monolayers. Expanded by 3D and co-culture, the P8-D6 treated cells were examined for changes in cytotoxicity, apoptosis rate and membrane integrity via scanning electron microscopy (SEM). Likewise, the effects of P8-D6 on non-cancer human ovarian surface epithelial cells and primary human hepatocytes were determined. Results: This study shows a significant P8-D6-induced increase in apoptosis and cytotoxicity in OvCa cells which surpasses the efficacy of standard therapeutic drugs. Non-cancer cells were affected only slightly by P8-D6. Moreover, no hepatotoxic effect in in vitro studies was detected.Conclusions: P8-D6 is a strong and rapid inductor of apoptosis and might be a novel treatment option for OvCa therapy.

Effects of long-term norepinephrine treatment on normal immortalized ovarian and fallopian tube cells

Sustained adrenergic stimulation by norepinephrine (NE) contributes to ovarian carcinoma metastasis and impairment of chemotherapy response. Although the effect of sustained NE stimulation in cancer progression is well established, less is known about its role in cancer initiation. To determine the extent to which stress hormones influence ovarian cancer initiation, we conducted a long-term (> 3 months; > 40 population doublings) experiment in which normal immortalized fallopian tube secretory (iFTSEC283) and ovarian surface epithelial (iOSE11) cell lines and their isogenic pairs containing a p53 mutation (iFTSEC283p53R175H; iOSE11p53R175H), were continuously exposed to NE (100 nM, 1 μM, 10 μM). Fallopian tube cells displayed a p53-independent increase in proliferation and colony-forming ability in response to NE, while ovarian surface epithelial cells displayed a p53-independent decrease in both assays. Fallopian tube cells with mutant p53 showed a mild loss of chromosomes and TP53 status was also a defining factor in transcriptional response of fallopian tube cells to long-term NE treatment.

HER-2 neu expression in surface epithelial ovarian tumors and its relationship with clinic-pathological parameters: a pilot study

Background: Ovarian cancer is one of the major source of morbidity and mortality in women among all gynecological malignancies. Her2/neu expression in ovarian carcinoma has not been studied extensively in ovarian surface epithelial carcinoma. It's can be utilized towards future proposed studies as a targeted therapy in new era of treatment for ovarian malignancies.Methods: It was a prospective study carried for 2 years. Hematoxylin and eosin stain was studied, grading, staging was evaluated for all the cases. Immunohistochemical staining with HER2/neu was done, evaluation done by 3 independent pathologists, correlation of HER2/neu with histological type, grade and stage was done. Results: The present study included 33 cases of histologically proven epithelial ovarian neoplasm with mean age of 44.5±25.55 years. Serous type constitutes majority of cases (48.48%), maximum number of cases was in high grade (57.57%) and high stage (40.74%). Majority of tumors showed negative expression of HER2/neu i.e. 42.42%. The current study found no significant correlation between HER2/neu expression and histological type, histological grade, extent of tumor (T stage) and distant metastasis. But we found a significant correlation between nodal metastasis and HER2/neu expression.Conclusions: HER2/neu therapy can be given in borderline and low grade tumor compared to high grade tumor.

Immunohistochemical Expression of Vascular Endothelial Growth Factor in Ovarian Surface Epithelial Neoplasms and its Association with Histological Type, Grade, Clinical Stage and Tumour Metastasis

Introduction: Ovarian carcinoma is one of the most common gynaecologic cancers and remains the leading cause of death as the patients are diagnosed at the advanced stage of the disease. Vascular Endothelial Growth Factor (VEGF), a promoter of angiogenesis, participates in multiple mechanisms to promote ovarian cancer cell growth, angiopoiesis and distant metastasis. So, it is a promising target for antiangiogenic therapy in management and downstaging of ovarian cancer. Aim: To evaluate the immunohistochemical expression of VEGF in different surface epithelial neoplasms of ovary and compare it with histological type, grade and stage in malignant cases. Materials and Methods: This was an observational cross-sectional study conducted from August 2018 to January 2020. Total 50 consecutive cases of surface epithelial ovarian neoplasms received in Pathology Department of Srirama Chandra Bhanja (SCB) Medical College, Cuttack were examined for expression of VEGF by Immunohistochemistry (IHC). Data was examined to find association of VEGF expression with demographic profile, grade, stage and were analysed statistically using Statistical Package for the Social Sciences (SPSS) software version 21.0. Statistical significance was tested by using Pearson’s chi-square test. The p<0.05 was considered significant. Results: Total 50 cases of ovarian surface epithelial neoplasms of different types and grade were included in the study. A 42 of the 50 cases (84%) showed VEGF expression. Out of the 42 positive cases, 18 were high VEGF expressors and 24 were low VEGF expressors. The VEGF expression was significantly higher in carcinomas as compared to benign and borderline neoplasms and also in high grade malignancies in comparison to low grade (p≤0.001). Conclusion: The study shows that the differential expression of VEGF in different ovarian epithelial neoplasms which can be a diagnostic and prognostic tool and can be applied as a VEGF targeted therapy in certain group of patients.

Metformin Reduces NGF-Induced Tumour Promoter Effects in Epithelial Ovarian Cancer Cells

Epithelial ovarian cancer (EOC) is a lethal gynaecological neoplasm characterized by rapid growth and angiogenesis. Nerve growth factor (NGF) and its high affinity receptor tropomyosin receptor kinase A (TRKA) contribute to EOC progression by increasing the expression of c-MYC, survivin and vascular endothelial growth factor (VEGF) along with a decrease in microRNAs (miR) 23b and 145. We previously reported that metformin prevents NGF-induced proliferation and angiogenic potential of EOC cells. In this study, we sought to obtain a better understanding of the mechanism(s) by which metformin blocks these NGF-induced effects in EOC cells. Human ovarian surface epithelial (HOSE) and EOC (A2780/SKOV3) cells were stimulated with NGF and/or metformin to assess the expression of c-MYC, β-catenin, survivin and VEGF and the abundance of the tumor suppressor miRs 23b and 145. Metformin decreased the NGF-induced transcriptional activity of MYC and β-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef), as well as the expression of c-MYC, survivin and VEGF in EOC cells, while it increased miR-23b and miR-145 levels. The preliminary analysis of ovarian biopsies from women users or non-users of metformin was consistent with these in vitro results. Our observations shed light on the mechanisms by which metformin may suppress tumour growth in EOC and suggest that metformin should be considered as a possible complementary therapy in EOC treatment.