naphthoquinones and Endometrial-Neoplasms

Clinically, evidence shows that uterine corpus endometrial carcinoma (UCEC) patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may have a higher death-rate. However, current anti-UCEC/coronavirus disease 2019 (COVID-19) treatment is lacking. Plumbagin (PLB), a pharmacologically active alkaloid, is an emerging anti-cancer inhibitor. Accordingly, the current report was designed to identify and characterize the anti-UCEC function and mechanism of PLB in the treatment of patients infected with SARS-CoV-2

Topics: Adult; Aged; Aged, 80 and over; Calcium-Binding Proteins; Carcinoma, Endometrioid; Computational Biology; COVID-19; COVID-19 Drug Treatment; Drug Screening Assays, Antitumor; Endometrial Neoplasms; Female; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genetic Association Studies; Host-Pathogen Interactions; Humans; Membrane Proteins; Middle Aged; Mitogen-Activated Protein Kinase 3; Molecular Docking Simulation; Naphthoquinones; Prognosis; SARS-CoV-2; Signal Transduction; Tumor Necrosis Factor-alpha; Uterus

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.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Cell Survival; Endometrial Neoplasms; Female; G2 Phase Cell Cycle Checkpoints; Humans; Naphthoquinones; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction

Ferroptosis is a novel iron-dependent cell death pathway mainly caused by an abnormal redox state and associated with various diseases including cancer. Recently, much attention has been paid to natural compounds that are involved in its activation and inhibition. This is the first ever study to demonstrate the role of juglone isolated from Carya cathayensis green peel in inducing autophagy and inhibiting endometrial cancer (EC) cell migration. Subsequently, Fe2+ accumulation, lipid peroxidation, GSH depletion, the upregulation of HMOX1, and heme degradation to Fe2+ were reported. Juglone was involved in inducing autophagy and inhibiting cell migration and endoplasmic reticulum stress, which are the new hallmarks of cancer treatment. Collectively, our data indicate that juglone as a functional food ingredient induces the programmed cell death of EC cells by activating oxidative stress and suggest a novel therapeutic approach for the treatment and prevention of EC.

Topics: Apoptosis; Autophagy; Carya; Cell Death; Cell Line, Tumor; Cell Movement; Endometrial Neoplasms; Female; Ferroptosis; Humans; Iron; Lipid Peroxidation; Naphthoquinones; Oxidation-Reduction; Oxidative Stress; Phagocytosis

The molecular mechanism of Juglone-induced cell cycle arrest and apoptosis in human endometrial cancer cells was investigated. Juglone was purified from the green husk of Carya cathayensis Sarg and identified by HPLC, LC-MS/MS, and NMR. At an IC

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carya; cdc25 Phosphatases; Cell Cycle Checkpoints; Cell Line, Tumor; Cyclin-Dependent Kinase 2; Endometrial Neoplasms; Female; Humans; Naphthoquinones; Plant Extracts

Several molecular targeting drugs are being evaluated for endometrial cancer; selecting patients whose cancers are sensitive to these agents is of paramount importance. Previously, we developed the cancer tissue-originated spheroid method for primary cancer cells taken from patients' tumors as well as patient-derived xenografts. In this study, we successfully prepared and cultured cancer tissue-originated spheroids from endometrial cancers. Characteristics of the original tumors were well retained in cancer tissue-originated spheroids including morphology and expression of p53 or neuroendocrine markers. We screened 79 molecular targeting drugs using two cancer tissue-originated spheroid lines derived from endometrioid adenocarcinoma grade 3 and serous adenocarcinoma. Among several hits, we focused on everolimus, a mammalian target of rapamycin complex 1 inhibitor, and YM155, a survivin inhibitor. When sensitivity to everolimus or YM155 was assessed in 12 or 11 cancer tissue-originated spheroids, respectively, from different endometrial cancer patients, the sensitivity varied substantially. The cancer tissue-originated spheroids sensitive to everolimus showed remarkable suppression of proliferation. The phosphorylation status of the mammalian target of rapamycin complex 1 downstream molecules before and after everolimus treatment did not predict the effect of the drug. In contrast, the cancer tissue-originated spheroids sensitive to YM155 showed remarkable cell death. The effect of YM155 was also confirmed in vivo. The histological type correlated with YM155 sensitivity; non-endometrioid adenocarcinomas were sensitive and endometrioid adenocarcinomas were resistant. Non-canonical autophagic cell death was the most likely cause of cell death in a sensitive cancer tissue-originated spheroid. Thus, sensitivity assays using cancer tissue-originated spheroids from endometrial cancers may be useful for screening drugs and finding biomarkers.

Topics: Animals; Apoptosis; Cell Proliferation; Drug Evaluation, Preclinical; Endometrial Neoplasms; Everolimus; Female; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Mechanistic Target of Rapamycin Complex 1; Mice; Molecular Targeted Therapy; Multiprotein Complexes; Naphthoquinones; Primary Cell Culture; Spheroids, Cellular; Survivin; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Survivin is an anti-apoptotic protein encoded by the baculoviral inhibitor of apoptosis repeat-containing (BIRC5) gene and is upregulated in 83% of endometrial cancers. We aimed to elucidate the prognostic importance of BIRC5 expression, and evaluate survivin as a therapeutic target for endometrial cancer, by knock-down of BIRC5 and using the survivin inhibitor-YM155.. RNA sequencing data in 234 patients with endometrial carcinoma was obtained from The Cancer Genome Atlas database, and analyzed using Kaplan-Meier method, log-rank test and Cox proportional hazard model. Expressions of survivin in 16 endometrial cancer cell lines were analyzed by western blotting. Knocking down effect on survivin expression was evaluated using a small interfering RNA (siRNA). The anti-proliferative and pro-apoptotic effects of YM155 were assessed with cell viability, flow cytometry, and annexin V/propidium iodide assays.. High expression of BIRC5 was associated with poor progression free survival (P=0.006), and shown to be an independent prognostic factor (HR=1.97, 95% CI=1.29-4.5, P=0.045). Survivin was upregulated in 14 of 16 (87.5%) endometrial cancer cell lines, compared with endometrial immortalized cells. Apoptosis was induced by knockdown of BIRC5 in all 3 cell lines examined. YM155 showed increased population of sub-G1 cells (P<0.001) in all 16 cell lines, and IC50 values to YM155 were <50nm in 15 cell lines. YM155 dose-dependently and significantly increased the apoptotic cell population in all 16 cell lines (P<0.001).. Present study indicated that survivin expression is a significant prognostic factor and that survivin is a promising therapeutic target for endometrial cancer.

Topics: Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Disease-Free Survival; Endometrial Neoplasms; Female; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Middle Aged; Molecular Targeted Therapy; Naphthoquinones; Prognosis; Survivin

SIRT6, a member of the sirtuin family, has been identified as a candidate tumor suppressor. To pursue the role of SIRT6 in endometrial cancer, we investigated the anti-tumorigenic function of SIRT6. The expression of SIRT6 negatively affected the proliferation of AN3CA and KLE endometrial cancer cells. Increased expression of SIRT6 resulted in the induction of apoptosis by repressing the expression of the anti-apoptotic protein survivin. Consistent with this result, a survivin inhibitor YM155 efficiently inhibited cellular proliferation and induced apoptosis. These results revealed that SIRT6 might function as a tumor suppressor of endometrial cancer cells.

Topics: Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Endometrial Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Immunohistochemistry; Inhibitor of Apoptosis Proteins; Kaplan-Meier Estimate; Naphthoquinones; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Sirtuins; Survivin; Tumor Suppressor Proteins

Beta-hydroxyisovalerylshikonin (beta-HIVS), a compound isolated from the traditional oriental medicinal herb Lithospermum radix, is an ATP non-competitive inhibitor of protein-tyrosine kinases, such as v-Src and EGFR, and it induces apoptosis in some lines of human tumor cells. We investigated the effect of beta-HIVS on three endometrial cancer cell lines, two ovarian cancer cell lines, and normal human endometrial epithelial cells.. Endometrial and ovarian cancer cells were treated with various concentrations of beta-HIVS, and its effect on cell growth, cell cycle, apoptosis, and related measurements was investigated.. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that all endometrial and ovarian cancer cell lines were sensitive to the growth-inhibitory effect of beta-HIVS, although normal endometrial epithelial cells were viable after treatment with the same doses of beta-HIVS that induced growth inhibition in endometrial and ovarian cancer cells. Cell-cycle analysis indicated that their exposure to beta-HIVS decreased the proportion of cells in the S phase and increased the proportion in the G0/G1 phases of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with altered expression of genes related to cell growth, malignant phenotype, and apoptosis.. These results suggest that the anticancer activity of beta-HIVS may occur with higher sensitivity of cancer cells compared with normal healthy cells, when using low concentration, rising hopes that beta-HIVS may become a useful adjuvant therapy for endometrial and ovarian cancers.

Topics: Apoptosis; Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Endometrial Neoplasms; Female; Humans; Intracellular Signaling Peptides and Proteins; Membrane Potential, Mitochondrial; Naphthoquinones; Ovarian Neoplasms; Up-Regulation