1 research outputs found
Identification of BMI1 Promoter Inhibitors from <i>Beaumontia murtonii</i> and <i>Eugenia operculata</i>
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 <i>Beaumontia murtonii</i> and <i>Eugenia
operculata</i> were selected as leads. Bioassay-guided fractionation
of the extracts led to the isolation of three known cardenolides (<b>1</b>–<b>3</b>) and one new compound (<b>4</b>) from <i>B. murtonii</i> and two known triterpenoids
(<b>5</b> and <b>6</b>) and one new compound (<b>7</b>) from <i>E. operculata</i>. These seven compounds
inhibited BMI1 promoter activity (IC<sub>50</sub> range 0.093–23.0
μM), and the most active compound, wallichoside (<b>1</b>), was further evaluated. Western blot analysis revealed that wallichoside
(<b>1</b>) decreases BMI1 protein levels in HCT116 human colon
carcinoma cells, and flow cytometry analysis showed that it significantly
reduced levels of the CSC biomarker epithelial cell adhesion molecule.
Wallichoside (<b>1</b>) also inhibited sphere formation of Huh7
human hepatocellular carcinoma cells, indicating that it diminished
the self-renewal capability of CSCs