PI3Kδ抑制剂CAL-101对骨髓瘤细胞的作用及与其他新型药物的协同效果初探  

Effect of PI3Kδ inhibitor CAL-101 on myeloma cell lines and preliminary study of synergistic effects with other new drugs

作　　者：张擎[1] 夏冰[1] 屈福莲[1] 袁田[1] 郭姗琦[1] 赵伟鹏[1] 李倩[1] 杨洪亮[1] 王亚非[1] 张翼鷟[1] 

机构地区：[1]天津医科大学肿瘤医院血液科,天津市肿瘤防治重点实验室,300060

出　　处：《中华血液学杂志》2014年第10期926-930,共5页Chinese Journal of Hematology

基　　金：天津市教委创新人才中青年骨干培养计划

摘　　要：目的 探讨磷脂酰肌醇3-激酶（PI3Kδ）抑制剂CAL-101对多发性骨髓瘤（multiple myeloma,MM）细胞增殖的影响及机制,为MM治疗提供新思路.方法 以MM细胞系U266、RPMI8226及MM患者骨髓瘤原代细胞为研究对象,用不同浓度CAL-101处理后,采用MTT法结合CalcuSyn软件分析细胞增殖抑制率,并观察CAL-101与PCI-32765、异羟肟酸（SAHA）、硼替佐米（BTZ）联合对MM细胞增殖的影响;Western blot法分析蛋白激酶B（AKT）、细胞外调节蛋白激酶（ERK）、磷酸化AKT （p-AKT）、磷酸化ERK（p-ERK）和PI3Kδ表达水平.结果 15、20、25、30、40μmol/L CAL-101作用于U266细胞48 h,细胞增殖抑制率分别为（33.54± 1.23）％、（41.72±1.78）％、（53.67±2.01）％、（68.97±2.11）％和（79.25±1.92）％,具有明显的剂量依赖性（P＜0.05）.对RPMI8226细胞的作用同对U266细胞的作用相似,亦呈明显的剂量依赖性.Western blot分析显示,U266、RPMI8226和MM原代细胞均可见AKT、ERK、p-AKT、p-ERK和PI3Kδ的表达;经CAL-101处理后,p-AKT和p-ERK的表达水平显著下调.CalcuSyn分析证实,对U266细胞,CAL-101与PCI-32765、SAHA、BTZ抑制细胞增殖具有协同作用,而对RPMI8226细胞,CAL-101与PCI-32765、BTZ抑制细胞增殖具有协同作用,协同指数小于1.结论 CAL-101可抑制MM细胞增殖.在MM细胞系及MM原代细胞均可见p-AKT、p-ERK、AKT、ERK和PI3Kδ的表达.CAL-101抑制MM细胞增殖的机制可能与下调p-AKT和p-ERK有关.CAL-101与MM一线治疗药物BTZ及新药PCI-32765、SAHA有显著协同抗MM效应.Objective To investigate the proliferation inhibitory role and mechanism of PI3K8 inhibitor CAL-101 on multiple myeloma （MM） cells, and to provide new therapeutic options for MM treatment. Methods MM cell lines U266 and RPMI8226 cells were treated with various concentrations of CAL-101. MTT assay and CalcuSyn software were performed to determine the inhibitory effect of CAL- 101 and the synergistic effect with PCI-32765, SAHA （suberoylanilide hydroxamic acid）, BTZ （Bortezomib） on MM cells. The protein expression level of p-AKT, p-ERK, AKT, ERK and PI3K5 processed by CAL-101 were analyzed by Western blot. Results CAL-101 at concentration of 15, 20, 25, 30 and 40μmol/L could induce significant dose-dependent proliferation inhibition on U266 cells after treatment for 48 hours. The cell proliferation inhibition rates were （ 33.54± 1.23 ） %, （41.72±1.78 ） %, （ 53.67± 2.01 ）%, （68.97±2.11 ）% and （79.25± 1.92）%, respectively. Similar results were found in RPMI8226 cell line. Western blots showed high expression level of p-AKT, p-ERK, AKT, ERK and PI3K8 in cell lines and MM primary cells, p-AKT and p-ERK protein expression levels were down-regulated significantly by CAL-101 treatment. Synergistic effect has been verified between CAL-101 and PCI-32765, SAHA and Bortezomib in U266 cell line, and PCI-32765, Bortezomib in RPMI8226 cell line with CI values less than 1. Conclusion CAL-101 could inhibit proliferation of MM cell lines. High levels of p-AKT, p-ERK, AKT, ERK and PI3K8 protein expression were observed in both cell lines and primary cells. Down-regulation of p-AKT and p-ERK probably related with the mechanism of CAL-101 in MM cell proliferation inhibition. CAL-101 has significant synergistic effect with PCI-32765, SAHA and BTZ.

关 键 词：多发性骨髓瘤 CAL-101 硼替佐米 药物协同作用 

分 类 号：R733.3[医药卫生—肿瘤]