| Summary: | 碩士 === 國立嘉義大學 === 生化科技學系研究所 === 104 === Leukemia, a malignant cancer, is caused by uncontroled proliferation of leukemic cells in circulation that transformed from bone marrow. Leukemia could be major divided into acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). For lymphocytic leukemia (LL) treatment, chemotherapy is the major strategy to reduce cancer cells, but caused poor prognosis and severe side effects. Lack of biomarkers restricted the efficiency of LL treatment. The phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of rapamycin (mTOR) pathway is constitutively activated in certain cancer cells. However, the exact regulation of PI3K-AKT-mTOR signaling on lymphocytic leukemia is still unclear. Therefore, this study analyzed the PI3Kα inhibitor BYL719, pan-PI3K inhibitor BKM120, mTORC1 inhibitor RAD001, mTORC1/C2 inhibitor AZD2014, and dual PI3K-mTOR inhibitors BEZ235, on regulating of mouse lymphocytic leukemia L1210 cells. Cell viability, cell cycle, and the related regulatory molecules were examined in PI3K-mTOR inhibitor-treated L1210 cells. The results showed that BYL719, BKM120, RAD001, AZD2014, and BEZ235 all decreased the viability of L1210 cells. By cell cycle analysis, RAD001, AZD2014, and BEZ235, but not BYL719 and BKM120, caused the cell cycle arrest at the G0/G1 phase. By western blot analysis, RAD001, AZD2014, and BEZ235 reduced the expression of Rictor, p-AKT, p-mTOR, p-S6, p-4EBP1, CDK4, and Cyclin D1. However, the apoptosis-related proteins Bak and cleavaged caspase 3 expression, as well as the sub-G1 level showed no significant difference. The expression of autophagy-related protein LC3 and the autophage index by acridine orange staining also showed no statistical difference. The results indicated that PI3K-AKT-mTOR inhibitors did not induced apoptosis nor autophagy in L1210 cells. Further analysis of the cell viability in human B-cell lymphoma Toledo cells with the treatment of PI3K-AKT-mTOR inhibitors, showing that BKM120, RAD001, AZD2014, and BEZ235 have the similar inhibitory effect. In conclusion, PI3K-AKT-mTOR pathway could regulate the growth of LL cells. Inhibitors target to PI3K-AKT-mTOR pathway might have inhibitory potential for LL treatment.
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