Oridonin phosphate-induced autophagy effectively enhances cell apoptosis of human breast cancer cells

Abstract

Oridonin is an active diterpenoid, which was extracted from traditional Chinese herbs and had been widely used in clinical treatment nowadays. Oridonin phosphate is one of the derivatives of oridonin. In the present study, we explored its anti-tumor effect and investigated the molecular mechanism of oridonin phosphate in breast cancer cell lines. Firstly, cell viability was analyzed by MTT assay. The breast cancer cells were treated with increasing concentrations of oridonin phosphate for 24, 48 and 72 h, respectively. The results demonstrated that oridonin phosphate inhibited the proliferation of MDA-MB-436 and MDA-MB-231 cells in a dose- and time-dependent manner. Next, cell apoptosis rate was detected in oridonin phosphate-treated breast cancer cells by Annexin V-FITC/PI dual staining analysis and the data demonstrated that oridonin phosphate induced cell apoptosis of breast cancer cells in time- and dose-dependent manner. Moreover, apoptosis-related proteins were detected by Western blotting analysis. The results showed that the expression level of Bax was up-regulated and the expression level of Bcl-2 was down-regulated. Meanwhile, the level of cleaved caspase-9 was significantly increased when the cells were treated with 40 μM of oridonin phosphate for 48 h, although the expression level of pro-caspase-9 was not obviously changed. All of the data revealed that mitochondrial apoptosis pathway may be involved in the cell apoptosis induced by oridonin phosphate in breast cancer cells. Importantly, the expression levels of autophagy-related protein beclin-1 and LC3-II were significantly higher in oridonin phosphate-treated breast cancer cell lines MDA-MB-436 and MDA-MB-231 for 48 h. Additionally, we further explored the relationship between apoptosis and autophagy specifically induced by oridonin phosphate in breast cancer cells. The result showed that inhibition of autophagy suppressed the cell apoptosis in oridonin phosphate-treated MDA-MB-436 cells. Taken together, the compound of oridonin phosphate simultaneously induced cell apoptosis and autophagy in breast cancer cells. Inhibition oridonin phosphate-induced cell autophagy suppressed the progression of cell apoptosis, which revealed that oridonin phosphate-induced autophagy participated in up-regulation of apoptosis in human breast cancer cells. It would provide some new clues for the therapy of breast cancer.

p53 Mediates Colistin-Induced Autophagy and Apoptosis in PC-12 Cells

“…In addition, p53 has been shown to play a critical role in autophagy modulation (38). Upon activation, autophagy may promote or inhibit apoptosis depending on the level of the insult, and the interplay between these two cellular processes has been the subject of intensive relationship (17,39). Associated with colistin therapy, nephrotoxicity and neurotoxicity remain poorly characterized adverse effects.…”

“…Autophagy participates in organelle turnover and in the bioenergetic management of starvation stresses, pathogen infection, and hypoxia in order to maintain cellular homeostasis (14,15). A number of stimuli can induce autophagy, apoptosis, or both, and recent studies suggest that autophagy delays or promotes apoptosis under certain conditions (16,17). For example, treatment of cells with pemetrexed and simvastatin promoted autophagy and inhibited apoptosis (16), while oridonin phosphate induced autophagy and enhanced apoptotic cell death (17).…”

“…A number of stimuli can induce autophagy, apoptosis, or both, and recent studies suggest that autophagy delays or promotes apoptosis under certain conditions (16,17). For example, treatment of cells with pemetrexed and simvastatin promoted autophagy and inhibited apoptosis (16), while oridonin phosphate induced autophagy and enhanced apoptotic cell death (17). However, the precise mechanisms that determine autophagy, apoptosis, and their interaction remain to be elucidated.…”

Autophagy Regulates Colistin-Induced Apoptosis in PC-12 Cells

“…Both autophagy and apoptosis are forms of programmed cell death and play important roles in homeostasis and diseases (17). Recent studies have suggested that autophagy may defer or promote the activation of apoptosis under certain circumstances (e.g., SIRT1 protects against apoptosis by promoting autophagy and oridonin phosphate-induced autophagy effectively enhances cell apoptosis) (18,19). Autophagy and apoptosis have a very complex relationship, and the precise mechanism remains to be determined.…”

Oridonin induces apoptosis and reverses drug resistance in cisplatin resistant human gastric cancer cells

“…1A), a bitter tetracyclin diterpenoid compound, may be isolated from Rabdosia rubescens, Isodon japonicus Hara and Isodon trichocarpus, which are widely distributed in China, Japan and Korea (7). Studies show that Ori exhibits potent anticancer activity against a wide range of cancer cell types, including those from prostate, breast, pancreatic and non-small cell lung cancer, leukemia, glioblastoma multiforme and human melanoma cells (8)(9)(10)(11)(12)(13). However, to the best of our knowledge, no study has shown the effect and the potential mechanism of Ori reversing MDR of human gastric cancer.…”