ABSTRACT
Colorectal cancer (CRC) is a common human malignancy, accounting for 600,000 death cases annually worldwide. Chrysophanol is a naturally occurring anthraquinone compound and exhibits anti-neoplastic activities. This study aims to explore the biological effects of chrysophanol on CRC metastasis and the relevant underlying mechanism. Cell proliferation assay, wound scratch assay, and Transwell invasion assay were used to examine the effect of chrysophanol on proliferation, migration, and invasion of CRC cells. Hypoxia-inducible factor-1α (HIF-1α) shRNA was utilized to transfect CRC cells to examine the role of HIF-1α in chrysophanol suppression of hypoxia-induced epithelial to mesenchymal transition (EMT). The suppression effect of chrysophanol on hypoxia-induced EMT in vivo was also validated in xenograft tumor models. In the present study, our findings indicated that chrysophanol has the capability to suppress hypoxia-induced EMT in CRC in vitro and in vivo, and the possible mechanism involved is the inhibition of HIF-1α via modulating PI3k/Akt signaling pathway. Collectively, the results indicated that chrysophanol can be used as an EMT and cancer metastasis inhibitor in the treatment of CRC. Anat Rec, 302:1561-1570, 2019. © 2019 American Association for Anatomy.
Subject(s)
Anthraquinones/pharmacology , Colorectal Neoplasms/pathology , Epithelial-Mesenchymal Transition/drug effects , Hypoxia/physiopathology , Mutagens/pharmacology , Animals , Apoptosis , Cell Movement , Cell Proliferation , Colorectal Neoplasms/drug therapy , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: To investigate the effect of ceramide monohexoside (CMH) on resistance to cisplatin and apoptosis in ovarian cell line COC1/DDP, and to provide new ideals and clues to seek new effective methods for studying the mechanism and reversing the resistance in ovarian cell line as well. METHODS: COC1 cells and COC1/DDP cells (before and after the treatment of mifepristone) were collected and neutral glycosphingolipids (N-GSLs) of the cells was isolated and purified, changes of CMH content were analyzed by high performance thin layer chromatography (HPTLC). The COC1/DDP cells were divided into three groups, one treated by cisplatin, one treated by mifepristone, the other treated by cisplatin and mifepristone. The survival rate of cells in three groups were evaluated by the methyl thiazolyl tetrazolium (MTT) assay, DNA ladders were presented by DNA gel electrophoresis, the forms of cells were observed by transmission electron microscope (TEM). RESULTS: The levels of CMH were (37.1 +/- 3.3)% in COC1/DDP, higher than that in COC1 (14.1 +/- 1.4)% (P < 0.001). After treating by 1.25, 5 micro mol/L mifepristone, the CMH were (26.6 +/- 2.6)% (P < 0.05) and (17.5 +/- 0.7)% (P < 0.001), respectively. Mifepristone had no effect on the viability of COC1/DDP cell below a concentration of 5 micro mol/L. But when mifepristone of 1.25 or 5 micro mol/L combined with cisplatin at a concentration of 0.1, 0.25, 0.5, 1.25, 2.5 micro g/ml, the inhibition rate of COC1/DDP cell is higher than that of COC1/DDP cells only treated by cisplatin at the concentration of 0.1 to 2.5 micro g/ml (P < 0.001). The combined treatment elicited DNA fragmentation, however, neither cisplatin of 1.25 micro g/ml nor mifepristone of 5 micro mol/L alone could potentiate DNA fragmentation. After the combined treatment, the COC1/DDP cells produced apoptosis body. CONCLUSIONS: CMH is related with resistance to cisplantin in ovarian cell line COC1/DDP. When CMH of COC1/DDP cells was inhibited by mifepristone, the cells were sensitive to cisplatin and apoptosis was elicited.
