YM155在腫瘤細(xì)胞化療增敏中的作用及機(jī)制研究
[Abstract]:Background: tumor is a common disease in the world, and malignant tumor is the most serious disease to human health. The most commonly known and harmful tumors in China are lung cancer, breast cancer, gastric cancer, liver cancer, cervical cancer, leukemia and so on. Among them, lung cancer is the most common and the highest mortality tumor. Breast cancer is the most common malignant tumor in Chinese women. The previous study of the research group found that the protein level of survivin, a member of the apoptosis inhibitor protein (inhibitor of apoptosis protein,IAP family, was up-regulated in adriamycin resistant and highly metastatic breast cancer cells. It is suggested that survivin plays an important role in the survival and metastasis of breast cancer. YM155, survivin targeted inhibitor can significantly down-regulate the expression of survivin in breast cancer cells. Therefore, we speculate that YM155 may play an important role in the survival of tumor cells and the treatment of malignant tumors by inhibiting survivin to promote apoptosis of tumor cells and increase the sensitivity of tumor cells to chemotherapeutic drugs. Objective: to detect the apoptosis-promoting effect of YM155 on four tumor cell lines (2 kinds of lung cancer cells and 2 kinds of breast cancer cells) with different biological characteristics. To detect whether YM155 enhances the sensitivity of tumor cells to paclitaxel (Paclitaxel,PAC), and to elucidate the possible causes and mechanisms of different sensitivity of different tumor cells to YM155. Method: 1. The effects of YM155 and paclitaxel on the proliferation of four kinds of tumor cells were detected by in vitro experiments such as MTT, clone formation. 2. In vitro experiments, such as MTT, clone formation, apoptosis, cell cycle and so on, were used to detect the effects of different concentrations of YM155 on the proliferation, apoptosis and cycle of four kinds of tumor cells. The sensitivity of the four tumor cells to YM155 was observed. 3. The changes of P53, survived, NF-魏 B pathway and other indexes were detected by in vitro experiments such as western blot,q RT-PCR, and the mechanism of YM155 promoting apoptosis and its sensitivity was analyzed. Results: both 1.YM155 and paclitaxel inhibited the proliferation of tumor cells and induced apoptosis. The effect of YM155 combined with paclitaxel on promoting apoptosis was significantly better than that of paclitaxel alone. The killing effect of 2.YM155 on tumor cells was concentration-dependent, and the killing effect on tumor cells also increased with the increase of concentration. The sensitivity of tumor cells with different p53 status to YM155 was also different. The sensitivity of p53 wild type tumor cells to YM155 was lower than that of p53 mutant or p53 deficient tumor cells. The effect of tumor cells with different 3.P53 states on the induction of MDM2 produced by YM155 is not the same. Under the stimulation of low concentration of YM155, the transcription level of MDM2 in p53 wild type tumor cells increased. YM155, as a target inhibitor of survivin, could specifically decrease the expression of survivin. Conclusion: 1.YM155 can increase the sensitivity of tumor cells to paclitaxel. The difference of sensitivity of tumor cells to YM155 in different state of 2.p53 is due to the regulation of p53 dependent MDM2.
【學(xué)位授予單位】:天津醫(yī)科大學(xué)
【學(xué)位級別】:博士
【學(xué)位授予年份】:2016
【分類號】:R730.53
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