digitoxigenin and Liver-Neoplasms

Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in diagnosis and more effective local therapies for primary cancer, the rate of metastatic death has not changed in the past forty years. In the present study, we made use of bioinformatics to analyze the data obtained from three public available microarray datasets on uveal melanoma in an attempt to identify novel putative chemotherapeutic options for the liver metastatic disease. We have first carried out a meta-analysis of publicly available whole-genome datasets, that included data from 132 patients, comparing metastatic vs. non metastatic uveal melanomas, in order to identify the most relevant genes characterizing the spreading of tumor to the liver. Subsequently, the L1000CDS

Topics: Aged; Cinnarizine; Clofazimine; Digitoxigenin; Drug Therapy; Female; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Male; Melanoma; Microarray Analysis; Middle Aged; Neoplasm Metastasis; Neoplasm Proteins; Uveal Neoplasms

B-Cell-specific Moloney murine leukemia virus insertion region 1 (BMI1) is a core component of the polycomb repressive complex 1 (PRC1). Abnormal expression of BMI1 is associated with a number of human malignances and cancer stem cells (CSCs), which cause chemotherapy resistance. Therefore, small molecules that inhibit BMI1 expression are potential candidates for cancer therapy. In this study, a cell-based reporter gene assay was developed that allowed BMI1 promoter activity to be measured in 293T human embryonic kidney cells based on luciferase expression levels. Using this screening assay, the methanol-soluble extracts of Beaumontia murtonii and Eugenia operculata were selected as leads. Bioassay-guided fractionation of the extracts led to the isolation of three known cardenolides (1-3) and one new compound (4) from B. murtonii and two known triterpenoids (5 and 6) and one new compound (7) from E. operculata. These seven compounds inhibited BMI1 promoter activity (IC

Topics: Animals; Antineoplastic Agents; Apocynaceae; Blotting, Western; Carcinoma, Hepatocellular; Cardenolides; Cell Line, Tumor; Eugenia; HCT116 Cells; HEK293 Cells; Humans; Inhibitory Concentration 50; Liver Neoplasms; Mice; Molecular Structure; Neoplastic Stem Cells; Plant Leaves; Polycomb Repressive Complex 1; Thailand; Triterpenes

QSAR analysis has been used to identify the essential structural requirements for increasing the inhibitory activities of selected bufadienolides from the Chinese drug Ch'an Su (and other sources) against the primary liver carcinoma cell line PLC/PRF/5 (PLC) and the derived colchicine-resistant line (COL). The variable substituent domain of the proposed pharmacophore of the bufadienolides was investigated using a Comparative Molecular Field Analysis (CoMFA) approach. A model with considerable predictive ability was obtained. In addition, the CoMFA results agreed well with the pharmacophore bufadienolide model for the parent PLC line proposed earlier.

Topics: Antineoplastic Agents; Bufanolides; Colchicine; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Liver Neoplasms; Models, Molecular; Quantitative Structure-Activity Relationship; Tumor Cells, Cultured