传统抗疟药氯喹协同地塞米松治疗急性淋巴细胞白血病的机制研究

地塞米松（Dex）等糖皮质激素是治疗急性淋巴细胞白血病（ALL）的首选药物，但因需长期大剂量使用而引发严重不良反应。因此，寻找协同Dex抗ALL的药物并阐述其作用机制，是ALL治疗领域的重大课题。申请者前期发现，传统抗疟药氯喹能协同Dex显著抑制Dex耐药ALL细胞株CEM-C1的增殖。进一步研究证实，氯喹与Dex联用上调糖皮质激素受体（GR）的蛋白质水平并抑制溶酶体功能，然而其分子机制尚未被阐明。因此，本项目拟在体外进一步验证氯喹协同Dex的抗ALL作用；采用荧光素酶报告基因法、激光共聚焦技术等手段，深入探讨氯喹协同Dex上调GR的机制；采用RNAi、基因敲除等技术阐明溶酶体功能抑制与GR上调的关系。最后在动物模型上验证氯喹协同Dex治疗ALL的作用。本项目的完成，有望为CQ与糖皮质激素联用治疗ALL等血液系统肿瘤提供理论依据，并为临床治疗ALL提供新靶点和新策略。

Glucocorticoids, such as dexamethasone, are among the most potent and effective agents in the treatment of acute lymphoblastic leukemia(ALL). However, glucocorticoids induce a range of side effects because of its long-term administration at high doses. Therefore, reasonable combination of agents with dexamethasone is an important strategy in the treatment of ALL. We found that combination of traditional antimalaria drug chloroquine with dexamethasone significantly inhibited the proliferation of dexamethasone-resistent ALL cell line CEM-C1. Furthermore, we found that combination of chloroquine with dexamethasone increased the abundance of glucocorticoid receptor and inhibited lysosomal function, whose mechanism is unknown. In this program, we plan to elucidate the relationship of lusosomal function and GR up-regulation by reporter gene assay, and laser scanning confocal microscope, and confirm the synergistic effect of chloroquine with dexamethasone in treating ALL in vivo. We believe that this program will lay the theoretical foundation of treatment of blood carcinoma such as ALL, and provide new target and treating strategy of ALL in clinical treatment.