Antiproliferative effect of ZSTK474 alone or in combination with chemotherapeutic drugs on HL60 and HL60/ADR cells.
Antiproliferative effect of ZSTK474 alone or in combination with chemotherapeutic drugs on HL60 and HL60/ADR cells.
复制标题
ZSTK474单独或联合化疗药物对HL60和HL60/ADR细胞的抗增殖作用
DOI：
10.18632/oncotarget.16589
复制
发表时间：
2017-06-13
期刊：
影响因子：
--
通讯作者：
Kong D
中科院分区：
文献类型：
--
作者：
Zhou Q;Chen Y;Zhang L;Zhong Y;Zhang Z;Wang R;Jin M;Gong M;Qiu Y;Kong D
化疗仍是急性髓系白血病（AML）临床治疗的主要手段之一，但多药耐药（MDR）已成为限制其疗效的严重问题。PI 3 K/Akt通路在调节细胞增殖和MDR中的重要作用提示PI 3 K抑制剂可能对AML的治疗有效。本研究观察了PI 3 K抑制剂ZSTK 474对AML细胞HL 60和阿霉素（ADR）耐药细胞HL 60/ADR的抗增殖作用。结果表明，ZSTK 474具有较强的抗增殖活性，诱导细胞周期阻滞于G1期，但未见明显凋亡。ZSTK 474还可剂量依赖性地影响细胞周期相关分子的蛋白水平，包括p27蛋白水平升高，cyclin D1蛋白水平降低，Rb蛋白磷酸化水平降低。ZSTK 474处理后，PI 3 K下游蛋白包括磷酸化PDK 1、Akt和GSK-3β以剂量依赖性方式减少。ZSTK 474可逆转HL 60/ADR细胞的耐药性，增加ADR在细胞内的蓄积，降低P-gp和MRP 1等多药耐药蛋白的表达和功能。ZSTK 474与化疗药物阿糖胞苷或长春新碱联合应用对HL 60和HL 60/ADR细胞有协同作用。综上所述，ZSTK 474对HL 60和HL 60/ADR细胞显示出有效的抗增殖作用;与阿糖胞苷或长春新碱联合使用产生协同作用。我们的研究结果表明ZSTK 474具有应用于AML患者治疗的潜力，但需要进一步的证据，特别是体内疗效。
While chemotherapy remains to be one of the main approaches in the clinical treatment of acute myeloid leukemia (AML), multidrug resistance (MDR) has become a serious problem which limits the therapeutic efficacy. The important roles of the PI3K/Akt pathway in modulating cell proliferation and MDR suggest that PI3K inhibitor might be effective for treatment of AML. In the present study, the antiproliferative effects of PI3K inhibitor ZSTK474 on AML cell HL60 and the adriamycin (ADR)-resistant HL60/ADR cells were investigated. Our data indicated that ZSTK474 exhibited potent antiproliferative activity, induced G1 cell cycle arrest, but no obvious apoptosis in both cell lines. Moreover, ZSTK474 affected the protein levels of cell-cycle-related molecules including increased p27, decreased cyclin D1 and phosphorylated Rb in dose-dependent manner. The proteins downstream of PI3K including phosphorylated PDK1, Akt and GSK-3β were reduced in a dose-dependent manner after ZSTK474 treatment. ZSTK474 reversed ADR resistance, increased the intracellular accumulation of ADR, and reduced the expression and function of multidrug resistance (MDR) proteins including both P-gp and MRP1 in HL60/ADR cells. The combination of ZSTK474 and chemotherapeutic drugs cytarabine or vincristine led to a synergistic effect in HL60 and HL60/ADR cells. In conclusion, ZSTK474 showed potent antiproliferative effect on HL60 and HL60/ADR cells; combination with cytarabine or vincristine resulted in synergistic effect. Our results suggest ZSTK474 has the potential to be applied in the treatment of AML patients, while further evidences particularly those about in vivo efficacy are needed.