Attitudes and barriers to participation in window-of-opportunity trials reported by White and Asian/Asian British ethnicity patients who have undergone treatment for endometrial cancer.

PURPOSE: Window-of-opportunity trials (WOT) are a study design that have been used to investigate drug activity in endometrial cancer (EC). Recruitment to cancer clinical trials by patients from ethnic minority groups is reported to be lower than for patients of White ethnicity. METHODS: A verbal questionnaire was conducted with White and Asian/Asian British ethnicity patients who had undergone treatment for EC. Strategic purposeful sampling was used to recruit patients from diverse social/educational backgrounds. Questions explored: background knowledge of clinical research, WOT study design, and views on medications that might be investigated. Thematic analysis was used to explore motivations for WOT participation and perceived barriers. RESULTS: In total, 21 patients were recruited to the study (15 White and 6 Asian/Asian British). Views on optimum time to receive trial information differed, preferences ranging from 'at the time of diagnosis' to 'a few days after diagnosis'. The choice of medication under investigation had a strong influence on potential willingness to participate, with greater interest reported in medications derived from vitamins or food supplements rather than hormone-based drugs. Potential barriers to participation included concern over potential side-effects and the emotional/physical burden of a cancer diagnosis prior to major surgery. DISCUSSION: This study provides important insights into patients' views on WOT participation in EC and raises issues that need to be considered for future trial design and participant recruitment materials. The timing and format of study information and type of substance under investigation were factors influencing potential participation. Future studies should consider using multi-lingual visual information videos to address information needs, as this may encourage participation by ethnic minority patients.

Icaritin inhibits endometrial carcinoma cells by suppressing O-GlcNAcylation of FOXC1.

BACKGROUND: Icaritin has a wide range of pharmacological activities, including significant an-titumor activity. However, the mechanism of action of icaritin in endometrial cancer (UCEC) remains unknown. FOX proteins are a highly conserved transcription factor superfamily that play important roles in epithelial cell differentiation, tumor metastasis, angiogenesis, and cell cycle regulation. FOXC1 is an important member of the FOX protein family. FOXC1 is aberrantly expressed in endometrial cancer and may play a role in the migration and invasion of endometrial cancer; however, its mechanism of action has not yet been reported. O-GlcNAc glycosylation is a common post-translational modification. In endometrial cancer, high levels of O-GlcNAcylation promote cell proliferation, migration, and invasion. Cancer development is often accompanied by O-GlcNAc modification of proteins; however, O-GlcNAc modification of the transcription factor FOXC1 has not been reported to date. PURPOSE: To investigate the inhibitory effects of icaritin on RL95-2 and Ishikawa endometrial cancer cells in vitro and in vivo and to elucidate the possible molecular mechanisms. METHODS/STUDY DESIGN: CCK8, colony formation, migration, and invasion assays were used to determine the inhibitory effects of icaritin on endometrial cancer cells in vitro. Cell cycle regulation was assayed by flow cytometry. Protein levels were measured based on western blotting. The level of FOXC1 expression in endometrial cancer tissues was determined by immunohistochemistry. To assess whether icaritin also has activity in vivo, its effect on tumor xenografts was evaluated. RESULTS: Immunohistochemical analysis of clinical samples revealed that FOXC1 expression was significantly higher in endometrial cancer tissues than in normal tissues. Downregulation of FOXC1 inhibited the proliferative, colony formation, migration, and invasive abilities of RL95-2 and Ishikawa endometrial cancer cells. Icaritin inhibited the proliferation, colony formation, migration, and invasion of endometrial cancer cells and blocked the cell cycle in S phase. Icaritin affected O-GlcNAc modification of FOXC1 and thus the stability of FOXC1, which subsequently triggered the inhibition of endometrial cancer cell proliferation. CONCLUSION: The anti-endometrial cancer effect of icaritin is related to the inhibition of abnormal O-GlcNAc modification of FOXC1, which may provide an important theoretical foundation for the use of icaritin against endometrial cancer.

Tanshinone IIA inhibits endometrial carcinoma growth through the MAPK/ERK/TRIB3 pathway.

Endometrial carcinoma is the most common gynecological tumor in developed countries. Tanshinone IIA is a traditional herbal medicine which is to treat cardiovascular disease and has been shown to have various biological effects, such as anti-inflammatory, antioxidative and antitumor activities. However, there has been no study about the effect of tanshinone IIA on endometrial carcinoma. Thus, the aim of this study was to determine the antitumor activity of tanshinone IIA against endometrial carcinoma and investigate the associated molecular mechanism. We demonstrated that tanshinone IIA induced cell apoptosis and inhibited migration. We further demonstrated that tanshinone IIA activated the intrinsic (mitochondrial) apoptotic pathway. Mechanistically, tanshinone IIA induced apoptosis by upregulating TRIB3 expression and inhibiting the MAPK/ERK signaling pathway. In addition, knockdown of TRIB3 with an shRNA lentivirus accelerated proliferation and attenuated inhibition mediated by tanshinone IIA. Finally, we further demonstrated that tanshinone IIA inhibited tumor growth by inducing TRIB3 expression in vivo. In conclusion, these findings suggest that tanshinone IIA has a significant antitumor effect by inducing apoptosis and may be used as a drug for the treatment of endometrial carcinoma.

MET Inhibits the Proliferation of EC Cells by Increasing MPA Sensitivity.

Context: The high resistance rate and high recurrence rate of progesterone only as a treatment for endometrial cancer (EC) limit its clinical application. Metformin (MET) may have antitumor ability. Combining MET and medroxyprogesterone acetate (MPA) may strengthen their inhibitory effects on proliferation of EC cells, but MET's mechanisms remain unclear. Objective: The study intended to identify the specific molecular mechanism that MET combined with MPA uses against EC progression. Design: The research team performed a controlled animal study. Setting: The study took place at Xuzhou Medical University in Xuzhou, China. Animals: The animals were16 female non-obese diabetic-severe combined immunodeficient (NOD-SCID) nude mice, about 12 to 16 g in weight. Interventions: The research team divided randomly, the mice into four groups and induced EC in all groups, four in each group: (1) The control group which received received normal saline, (2) the MPA group, which received 100 mg/kg of MPA; (3) the MET group, which received metformin at the rate of 200 mg/kg, each gavage volume was 0.1ml; (4) the MET+MPA group, which received 100 mg/kg of MPA and 200 mg/kg of MET. Outcome measures: The research team: (1) used a CCK-8 kit, an EdU assay, and a flow-cytometry assay to measure cancer-cell proliferation, count, and viability; determine the cell cycle; and measure apoptosis; (2) performed a Western blot analysis to determine the expression of the PR, CD133, pAkt, totalAkt, p-mTOR, and totalTOR antibodies; and (3) determined the size and volume of tumors in vivo and used immunohistochemical staining to determine expression of the Ki67 protein. Results: The MET+MPA group had a significantly lower number of cancer cells than the MET or MDA groups (both P < .001). That group also had significantly more stagnated cancer cells in the G0/G1 phase and significantly fewer cancer cells in the S phase or G2/M phase control, MET, or MPA groups (all P < .01). The MET+MPA group's PCNA and Ki-67 protein expression was significantly lower than that of the MET and MPA group. The EDU assay yielded similar results. Additionally, the MET+MPA group had significantly higher PR expression than that of to MET or MPA group (both P < .001). The MET and MPA groups' expression of CD133, p-Akt, and p-mTOR were significantly lower than those of the control group, while the MET+MPA group's levels were significantly lower than those of the MET and MPA groups. In-vivo experiments revealed that the MET and MPA groups did show decreased tumor size and volume. The MET+MPA group had tumor weights that were significantly lower and tumor volumes were significantly smaller than those of the MET and MPA groups (all P < .001). Immunohistochemical analysis revealed that the MET+MPA group's levels of the Ki-67 antigen were significantly lower than those of the MET and MPA groups. Conclusions: MET inhibited the proliferation of EC cells by increasing MPA-sensitivity, which was dependent on the inhibition of the CD133 expression and the Akt/mTOR pathway. In addition, if MET acts as an effective progestin sensitizer, it certainly offers promising therapeutic prospects for patients with early-stage EC or overgrown endometrium who have fertility requirements.

Biomarker-driven therapy in endometrial cancer.

This article reviews treatments and targets of interest in endometrial cancer by molecular subtype. The Cancer Genome Atlas (TCGA) classifies four molecular subtypes-mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H); copy number high (CNH)/p53abn; copy number low (CNL)/no specific molecular profile (NSMP); and POLEmut-which are validated and highly prognostic. Treatment consideration by subtype is now recommended. In March and April 2022, respectively, the US Food and Drug Administration (FDA) fully approved and the European Medicines Agency adopted a positive opinion recommending the anti-programmed cell death protein-1 (PD-1) antibody pembrolizumab for advanced/recurrent dMMR/MSI-H endometrial cancer which has progressed on or following a platinum-containing therapy. A second anti-PD-1, dostarlimab, received accelerated approval by the FDA and conditional marketing authorization by the European Medicines Agency in this group. The combination of pembrolizumab/lenvatinib for mismatch repair proficient/microsatellite stable endometrial cancer, including p53abn/CNH and NSMP/CNL, received accelerated FDA approval in conjunction with Australia's Therapeutic Goods Administration and Health Canada in September 2019. The FDA and European Medicines Agency made full recommendations in July 2021 and October 2021. Trastuzumab is National Comprehensive Cancer Network (NCCN) compendium listed for human epidermal growth factor receptor-2-positive serous endometrial cancer, which is primarily within the p53abn/CNH subtype. In addition to hormonal therapy, maintenance therapy with selinexor (exportin-1 inhibitor) showed potential benefit in p53-wildtype cases in a subset analysis and is being investigated prospectively. Other treatment regimens being evaluated in NSMP/CNL are hormonal combinations with cyclin-dependent kinase 4/6 inhibitors and letrozole. Ongoing trials are evaluating immunotherapy in combination with frontline chemotherapy and other targeted agents. Treatment de-escalation is being evaluated in POLEmut cases given its favorable prognosis with or without adjuvant therapy. Molecular subtyping has important prognostic and therapeutic implications, and should guide patient management and clinical trial design in endometrial cancer, which is a molecularly driven disease.

Integrated miRNA and mRNA omics reveal dioscin suppresses migration and invasion via MEK/ERK and JNK signaling pathways in human endometrial carcinoma in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonatum sibiricum Redouté (PS, also called Huangjing in traditional Chinese medicine), is a perennial herb as homology of medicine and food. According to the traditional Chinese medicine theory "Special Records of Famous Doctors", its functions include invigorating qi and nourishing yin, tonifying spleen and kidney. Traditionally, qi and blood therapy has been believed as most applicable to the treatment of uterine disease. The current research has focused on the effect and mechanism of dioscin, the main active component of PS, on Endometrial carcinoma (EC). AIM OF THE STUDY: To study the efficacy of dioscin on proliferation and migration of Endometrial carcinoma cell line, we conducted experiments by using xenograft model and Ishikawa cells, and explored the potential molecular mechanism. MATERIALS AND METHODS: mRNA and miRNA omics techniques were employed to investigate the regulatory mechanism of dioscin on EC Ishikawa cells. Based on in vivo and in vitro experiments, cell clone formation, cell scratching, Transwell, H&E staining, immunohistochemistry, q-PCR, and Western blot techniques were used to determine the molecular effects and mechanisms of dioscin on cell migration. RESULTS: Integrated miRNA and mRNA omics data showed that 513 significantly different genes marked enrichment in MAPK signaling pathway. The in vivo data showed that dioscin (24 mg/kg) significantly inhibited tumor growth. The in vitro proliferation and invasiveness of dioscin on Ishikawa cells showed that dioscin could significantly decrease the colony numbers, and suppress the Ishikawa cell wound healing, migration and invasion. Molecular data revealed that dioscin decreased the MMP2 and MMP9 expression in vitro and in vivo. The p-MEK, p-ERK, and p-JNK expression levels were also confirmed to be significantly reduced. Key regulators in the MAPK signaling pathway were further validated in xenograft tumors. CONCLUSION: Our data indicated that dioscin inhibited Ishikawa cell migration and invasion mediated through MEK/ERK and JNK signaling. More importantly, screened hub miRNAs and genes can be regarded as potential molecular targets for future EC treatment.

Transcriptome and proteomics conjoint analysis reveal metastasis inhibitory effect of 6-shogaol as ferroptosis activator through the PI3K/AKT pathway in human endometrial carcinoma in vitro and in vivo.

Endometrial cancer remains as one of the widespread female malignancies despite the existing treatment measures mainly surgery, radiotherapy, and chemotherapy. In recent times, studies have focused on medicinal plants such as ginger due to its multifaceted characteristics compared to conventional medicine. 6-Shogaol is regarded as the main active compound of ginger participating in pharmacological activities and combating various health disorders, especially cancer. In our study, we compared the effects of 6-gingerol, 6-paradol, and 6-shogaol on Ishikawa cells, and found 6-shogaol as a more effective ingredient against Ishikawa cell proliferation. Moreover, its promoted ferroptosis, as a result, triggered mitochondrial morphologic alternation, as well as changed iron concentration, GSH and MDA levels. Furthermore, 6-Shogaol inhibited cell metastasis by influencing cell invasion and migration. Finally, 6-shogaol could trigger PI3K/AKT signaling pathways in vitro and in vivo confirmed by western blotting assay and immunohistochemical evaluation. These findings suggest that 6-shogaol can be used as promising functional food component in health diet and in drug target methods for endometrial cancer therapy.

Exploration of the Effect and Potential Mechanism of Echinacoside Against Endometrial Cancer Based on Network Pharmacology and in vitro Experimental Verification.

Background: Endometrial cancer (EC) is one of the most common gynecological malignancies, especially in postmenopausal women. Echinacoside (ECH) is a major natural bioactive ingredient derived from Cistanches Herba and Echinacea that has a variety of pharmacological effects. However, the efficacy and the mechanism of ECH against EC have not been elucidated yet. Purpose: A compound-target-disease network was constructed to explore the potential targets and mechanism of ECH against EC. Molecular docking and in vitro experiments further verified the effect of ECH against EC. Methods: The potential targets of ECH against EC were retrieved from multiple public databases. Then, the protein-protein interaction (PPI) network was constructed to screen hub targets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to discover the potential mechanism. Molecular docking was utilized to verify the binding affinity between hub targets and ECH. Finally, in vitro experiments were conducted to demonstrate the anti-EC effect of ECH. Results: A total of 110 genes were identified as potential targets of ECH against EC. The GO enrichment analysis found that targets were primarily related to oxygen species, apoptosis, and other physiological processes. KEGG pathway analysis showed that PI3K/Akt signaling pathways might play an important role in ECH against EC. Molecular docking indicated that ECH had a significant binding ability with the EGFR, AKT1, ESR1, CASP3, HSP90AA1and MMP9 targets. Results from in vitro experiments revealed that ECH induced apoptosis of Ishikawa and HEC-1-B cells by promoting the arrest of the G2M phase, increasing ROS levels, and decreasing mitochondrial membrane potential (MMP) levels. Furthermore, treatment of ECH significantly reduced the expression levels of PI3K and p-AKT, and the combination of the PI3K inhibitor (LY294002) further enhanced the effects of ECH against EC. The findings suggested that ECH exerted an inhibitory effect on EC cells by inhibiting the PI3K/AKT pathway. Conclusion: Based on network pharmacology, molecular docking technology and in vitro experiments, we comprehensively clarified the anti-EC efficacy of ECH through multiple targets and signal pathways. Furthermore, we provided a novel idea of Traditional Chinese medicine (TCM) against EC.

Antioxidative, Anti-Inflammatory, Anti-Obesogenic, and Antidiabetic Properties of Tea Polyphenols-The Positive Impact of Regular Tea Consumption as an Element of Prophylaxis and Pharmacotherapy Support in Endometrial Cancer.

Endometrial cancer (EC) is second only to cervical carcinoma among the most commonly diagnosed malignant tumours of the female reproductive system. The available literature provides evidence for the involvement of 32 genes in the hereditary incidence of EC. The physiological markers of EC and coexisting diet-dependent maladies include antioxidative system disorders but also progressing inflammation; hence, the main forms of prophylaxis and pharmacotherapy ought to include a diet rich in substances aiding the organism's response to this type of disorder, with a particular focus on ones suitable for lifelong consumption. Tea polyphenols satisfy those requirements due to their proven antioxidative, anti-inflammatory, anti-obesogenic, and antidiabetic properties. Practitioners ought to consider promoting tea consumption among individuals genetically predisposed for EC, particularly given its low cost, accessibility, confirmed health benefits, and above all, suitability for long-term consumption regardless of the patient's age. The aim of this paper is to analyse the potential usability of tea as an element of prophylaxis and pharmacotherapy support in EC patients. The analysis is based on information available from worldwide literature published in the last 15 years.

The Efficacy of Psychological Care and Chinese Herbal Decoction in Postoperative Chemotherapy Patients with Endometrial Cancer.

BACKGROUND: In recent years, the incidence of endometrial cancer (EC) has been on the rise worldwide. The purpose of this study was to investigate the efficacy of psychological care and Chinese herbal decoction in EC patients with postoperative chemotherapy. METHODS: 80 EC patients with postoperative chemotherapy were randomly divided into the observation group and control group. The control group was given psychotherapy. The observation group was given psychological care plus Chinese herbal decoction treatment. HE4, CA125, traditional Chinese medicine (TCM) syndrome scores, toxic and side effects, and quality of life scores before and after treatment were observed. RESULTS: After treatment, the total effective rate of the observation group was higher than that of the control group. After treatment, serum HE4 and CA125 levels in the observation group were lower than those in the control group. In addition, CD3+ and CD4+ levels in the observation group were higher than those in the control group. Meanwhile, the CD8+ level in the observation group was lower than that in the control group. Compared with the control group, the quality of life in the observation group was significantly improved, and the incidence of adverse reactions was reduced. CONCLUSION: Chinese herbal decoction combined with psychological care can improve the clinical symptoms, alleviate the toxic and side effects, and improve the life quality of EC patients with postoperative chemotherapy.

Synergistic Growth Inhibitory Effects of Eryngium kotschyi Extracts with Conventional Cytotoxic Agents: Cisplatin and Doxorubicin against Human Endometrium Cancer Cells.

BACKGROUND: Endometrial cancer is one of the most common types of cancer. For this reason, various studies have been carried out on its treatment and the effects of natural products on this disease. OBJECTIVES: This study aimed to examine the growth inhibitory effects of Eryngium kotschyi Boiss. ethyl acetate [EKE] and butanol [EKB] obtained from the main methanol [EKM] extract from the aerial parts on human endometrium carcinoma [RL95-2] cells and their synergistic effect with cisplatin or doxorubicin. METHODS: RL95-2 cells were treated with E. kotschyi extracts either alone or in combination with cisplatin or doxorubicin. The effects on cell growth were determined using the MTT assay and real-time cell analysis xCELLigence. RESULTS: The extracts demonstrated growth inhibitory activity, with a certain degree of selectivity against the RL95-2 cell line. Synergistic effects of EKE/cisplatin or doxorubicin at different concentration levels were demonstrated in RL95-2 cells. In some instances, the EKE/doxorubicin combinations resulted in antagonistic effects. The reduction level of cell viability was different and specific to each combination for the RL95-2 cell line. CONCLUSION: The growth inhibitory activity of cisplatin or doxorubicin, as a single agent, may be modified by combinations of the extracts and be synergistically enhanced in some cases. A significant synergistic effect of EKE on the RL95-2 cell line with cisplatin and doxorubicin was observed. This cytotoxic effect can be investigated in terms of molecular mechanisms. This study is the first of its kind in the literature. The mechanisms involved in this interaction between chemotherapeutic drugs and plant extracts remain unclear and should be further evaluated.

Network Pharmacology-Based and Molecular Docking Analysis of Resveratrol's Pharmacological Effects on Type I Endometrial Cancer.

BACKGROUND: Resveratrol is a natural polyphenol commonly seen in foods. It has demonstrated an inhibitive effect on endometrial cancer, but the molecular action is still not known. OBJECTIVE: We aimed to use network pharmacology to systematically study the possible mechanisms of resveratrol's pharmacological effects on type I endometrial cancer. METHODS: Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) were used to predict resveratrol's possible target genes. They were then converted to UniProt gene symbols. Simultaneously, type I endometrial cancer-related target genes were collected from GeneCards. All data were pooled to identify common target genes. The protein-protein interaction (PPI) network was constructed and further analyzed via STRING Online Database. Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were also performed afterward. To visualise resveratrol's overall pharmacological effects on type I endometrial cancer, a network of drug components-target gene-disease (CTD) was constructed. Then, we performed in silico molecular docking study to validate the possible binding conformation between resveratrol and candidate targets. RESULTS: There are 150 target genes of resveratrol retrieved after UniProt conversion; 122 of them shared interaction with type I endometrial cancer. Some important oncogenes and signaling pathways are involved in the process of resveratrol's pharmacological effects on endometrioid cancer. Molecular docking analysis confirmed that hydrogen bonding and hydrophobic interaction are the main interaction between resveratrol and its targets. CONCLUSION: We have explored the possible underlying mechanism of resveratrol in antagonising type I endometrial cancer through a network pharmacology-based approach and in-silico verification. However, further experiments are necessary to add to the evidence identifying resveratrol as a promising anti-type I endometrial cancer agent.

Histone Deacetylase Inhibitors: A Promising Therapeutic Alternative for Endometrial Carcinoma.

Endometrial carcinoma is the most common malignant tumor of the female genital tract in the United States. Epigenetic alterations are implicated in endometrial cancer development and progression. Histone deacetylase inhibitors are a novel class of anticancer drugs that increase the level of histone acetylation in many cell types, thereby inducing cell cycle arrest, differentiation, and apoptotic cell death. This review is aimed at determining the role of histone acetylation and examining the therapeutic potential of histone deacetylase inhibitors in endometrial cancer. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms histone deacetylase, histone deacetylase inhibitor, and endometrial cancer were employed, and we were able to identify fifty-two studies focused on endometrial carcinoma and published between 2001 and 2021. Deregulation of histone acetylation is involved in the tumorigenesis of both endometrial carcinoma histological types and accounts for high-grade, aggressive carcinomas with worse prognosis and decreased overall survival. Histone deacetylase inhibitors inhibit tumor growth, enhance the transcription of silenced physiologic genes, and induce cell cycle arrest and apoptosis in endometrial carcinoma cells both in vitro and in vivo. The combination of histone deacetylase inhibitors with traditional chemotherapeutic agents shows synergistic cytotoxic effects in endometrial carcinoma cells. Histone acetylation plays an important role in endometrial carcinoma development and progression. Histone deacetylase inhibitors show potent antitumor effects in various endometrial cancer cell lines as well as tumor xenograft models. Additional clinical trials are however needed to verify the clinical utility and safety of these promising therapeutic agents in the treatment of patients with endometrial cancer.

Mechanism of Tetrandrine Against Endometrial Cancer Based on Network Pharmacology.

BACKGROUND: Endometrial cancer (EC) is one of the most common gynaecological malignancies, and its incidence has been rising over the past decade. Tetrandrine, a bisbenzylisoquinoline alkaloid, has been isolated from a vine used in traditional Chinese medicine, Stephania tetrandra. However, the key mechanism of tetrandrine in EC is still unclear. PURPOSE: This research was designed to predict the molecular mechanisms of tetrandrine against EC based on network pharmacology and to further verify these predictions by in vitro experiments. METHODS: The potential therapeutic targets of tetrandrine against EC were predicted by using public databases. Afterwards, the protein-protein interaction (PPI) network of the common targets was constructed, and the key gene targets were obtained. Biological function and pathway enrichment analyses were performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Furthermore, molecular docking and in vitro experiments were carried out to verify the predictions. The cell counting kit­8 (CCK­8) assay, Hoechst 33258 staining, flow cytometry analysis, qRT-PCR, Western blot analysis and an immunofluorescence assay were performed. RESULTS: Our findings identified 111 potential therapeutic targets of tetrandrine against EC. We obtained 7 key gene targets from the PPI network analysis. Furthermore, GO enrichment analysis indicated that these targets were mainly associated with metabolic processes, responses to stimulus, and biological regulation. The KEGG pathway analysis showed that the common targets were mainly distributed in the PI3K/Akt signalling pathway. A potential interaction of tetrandrine with Akt1 was revealed by molecular docking. In addition, in vitro experiments showed that tetrandrine significantly inhibited cell proliferation and induced apoptosis in Ishikawa and HEC-1-B cells in dose- and time-dependent manners. The results also revealed that tetrandrine can downregulate the expression of Bcl-2 and upregulate the expression of Bax at the mRNA level. The mRNA levels of Akt were not significantly different in the various tetrandrine (0, 10 and 20µM) groups. However, Western blot analysis demonstrated that the protein expression ratios of p-Akt/Akt decreased at the protein level. The results were further confirmed by immunofluorescence assays. CONCLUSION: Based on bioinformatic analysis and experimental verification, our findings demonstrated that tetrandrine exerted tumour-suppressive effects on EC by regulating the PI3K/Akt signalling pathway.

Preliminary evaluation on the beneficial effects of pioglitazone in the treatment of endometrial cancer.

Endometrial cancer (EMC) is one of the complicated gynecological cancers, affecting more than three million women worldwide. Anticancer strategies such as chemotherapy, radiation, and surgery are found to be ineffective and are associated with patient incompliances. The aim of the present study is to repurpose non-oncological drug, i.e., Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, in the treatment of endometrial cancer. The study groups consist of 50 female Swiss albino mice, out of which 40 had endometrial cancer induced with N-ethyl-N-nitrosourea (ENU) and estradiol hexadrobenzoate (EHB). The other groups received saline, EHB, paclitaxel, and different test doses of pioglitazones. Different preliminary parameters such as weekly body weight, mean survival time, percentage increase in life span, and uterine tissue weight were analyzed along with histopathological analysis. We observed a significant change in weekly body weight, improvement in percentage life span, and partial restoration of uterine tissue weight to normal compared to a standard drug, paclitaxel. In the present preliminary evaluation, we have identified that pioglitazone exhibited a significant dose-dependent anticancer activity against ENU- and EHB-induced endometrial cancer, compared to the standard paclitaxel.

The Promotional Effect of Hollow MnO2 with Brucea Javanica Oil Emulsion (BJOE) on Endometrial Cancer Apoptosis.

Endometrial cancer (EC) is a common gynecological malignancy worldwide whose therapy mainly depends on chemotherapy. In past years, an increasing number of studies indicate that hollow MnO2 could serve as a nanoplatform in the drug delivery system. The Brucea javanica oil emulsion (BJOE) has been illustrated to play a vital role in cancers. However, knowledge about the combined effect of H-MnO2-PEG/BJOE in endometrial cancer remains ambiguous up to now. In the present work, we prepared a drug-delivery vector H-MnO2-PEG by chemical synthesis and found that H-MnO2-PEG significantly inhibited cell proliferation in endometrial cancer cells. Moreover, the combination of H-MnO2-PEG/BJOE could repress cell proliferation more efficiently and promote cell apoptosis. Mechanistically, we found that BJOE exerted its role as a promoter of endometrial apoptosis by regulating relative protein expressions. In general, the present study demonstrates that H-MnO2-PEG functions as a critical vector in the tumor microenvironment of endometrial cancer and the significant effect of H-MnO2-PEG/BJOE on cancer cells, suggesting a new paradigm for the treatment of endometrial cancer.

Adlay Testa (Coix lachryma-jobi L. var. Ma-yuen Stapf.) Ethanolic Extract and Its Active Components Exert Anti-Proliferative Effects on Endometrial Cancer Cells via Cell Cycle Arrest.

Endometrial cancer is the most common malignant tumors of gynecologic neoplasms in Western society. In recent years, the incidence of endometrial cancer has increased, and it has become the third most common female gynecological cancer (after ovarian and cervical cancer) in Taiwan. Adlay (Coix lachryma-jobi L. var. Ma-yuen Stapf.) has been demonstrated to have bioactive polyphenols, flavonoids, phytosterols, and essential nutrients for health benefits, including anticancer effects in humans. However, little is known about the effect of adlay seeds on endometrial cancer. Our study aimed to investigate the potential growth inhibitory effects of several adlay seed fractions, including ethyl acetate (ATE-EA) and its bioactive constituents, separately on endometrial cancer cells-HEC-1A (phosphatase and tensin homolog-positive) and RL95-2 (phosphatase and tensin homolog-negative)-and identify related active ingredients. In addition, the potential active fractions and the phytochemical compounds were elucidated. The results demonstrate superior activity of ATE-EA with significant in vitro cell proliferation inhibitory capacity, particularly its C.D.E.F-subfraction. Moreover, HPLC- and GC/FID-based quantification of ATE-EA subfractions showed that phenolic compounds (caffeic acid, protocatechuic acid, and p-hydroxybenzaldehyde), flavonoids, steroids, and fatty acid compounds exert anti-proliferative effects in the cell model. Finally, it was shown that cell growth and cell cycle arrest most significantly occurred in the in G1 or G2/M phase under ATE-EA treatment. Collectively, our results demonstrate an antiproliferative effect of ATE-EA on endometrial cancer cells that suggest a positive health outcome for women from consumption of these compounds.

Hydroethanolic Extracts of the Aristotelia Chilensis (Maqui) Berry Reduces Cellular Viability and Invasiveness in the Endometrial Cancer Cell Line Ishikawa.

Cancer of the reproductive tract includes diseases with higher prevalence in the female population. This investigation examined whether an anthocyanin-enriched extract of Aristotelia chilensis, commonly known as "maqui," could affect some hallmarks of endometrial cancer. Cultures of the human endometrial cancer cell line Ishikawa were treated with a hydroethanolic maqui extract at 1, 3, 10, 30, 100, 300, or 1000 µg/mL to determine the effect on cell viability by MTT assay. Then, we used the 50% Effective Concentration (EC50) to evaluate whether the effect of the maqui extract is mediated via an arrest of the cell cycle or induction of apoptosis using flow cytometry or Annexin V-FITC assays, respectively. The effects of sublethal doses of the maqui extract on migration and invasiveness of Ishikawa cells were also evaluated by the wound healing and Boyden Chamber assay, respectively. Our results show that the hydroethanolic maqui extract inhibits the cell viability with an EC50 of 472.3 µg/mL via increased apoptosis, and that reduces the invasive capacity but not migration of Ishikawa cells. These findings suggest that the hydroethanolic maqui extract has antineoplastic properties for endometrial cancer and merits further studies to corroborate its efficiency as anticancer therapy in reproductive organs.

Asparanin A inhibits cell migration and invasion in human endometrial cancer via Ras/ERK/MAPK pathway.

Asparanin A (AA), a natural compound present in vegetables and medicinal herbs like Asparagus officinalis L., has been investigated extensively for its pharmacological attributes. So far, the effect of AA on endometrial cancer (EC) cell migration and invasion has not been explored. Herein, we elucidated the anti-metastasis mechanism of AA on Ishikawa cells based on miRNA-seq and mRNA-seq integrated analyses. AA treatment led to altered miRNAs expression in Ishikawa cells and inhibited the cell wound healing, cell migration and invasion. Gene Ontology and KEGG enrichment analyses showed that the target genes of different expression miRNAs were significantly enriched in Ras, Rap1 and MAPK signaling pathways. Further verification of these changes via qRT-PCR and Western blot assays in vitro and in vivo demonstrated that AA could suppress human EC cell migration and invasion through Ras/ERK/MAPK pathway. Furthermore, top two miRNAs (miR-6236-p5 and miR-12136_R+8) and top three target genes (KITLG, PDGFD, and NRAS) were identified as functional hub miRNAs and genes through miRNA-target gene network analysis. Our data presented a holistic approach to comprehend the anti-metastatic role of AA in EC after in vitro and in vivo analyses.

Plumbagin induces Ishikawa cell cycle arrest, autophagy, and apoptosis via the PI3K/Akt signaling pathway in endometrial cancer.

Plumbagin (PLB) is a naphthoquinone endowed with potential medicinal properties, including anticancer activities. We evaluated the effects of PLB on the viability, cell cycle, autophagy, and apoptosis of endometrial carcinoma Ishikawa cells. The proliferation of cells was significantly inhibited by PLB at 0, 8, 10, and 12 µM. By up regulating the expression of p53 and p21, PLB could block the cell cycle in G2/M phase and down regulate cyclin dependent kinase. The apoptosis in the cancer cells was characterized by noticeable chromatin edge collection, nuclear membrane expansion, and vacuolization. PLB could significantly induce autophagy in cells, and its inhibition ability and apoptosis induction were weakened by the autophagy inhibitor SBI-0206965. Our study suggested that PLB may exert anticancer effects by abrogating PI3K/Akt pathway, which recommends it as a promising future phytotherapeutic candidate for EC treatment.