Abstract

Context

A portion of patients with chronic myeloid leukaemia (CML) develop resistance to the Bcr-Abl tyrosine kinase inhibitors (TKIs), limiting the clinical applications. Previous results have demonstrated the synergistic effects between cryptotanshinone (CPT) and imatinib on apoptosis of CML cells in vitro.

Objective

To determine the antileukemia effects of CPT and TKIs on the resistant CML cells, and further investigate the effect of combined treatment of CPT and imatinib on tumour growth and apoptosis in the xenograft model and clarify its regulatory mechanisms.

Materials and methods

The combination effects of CPT and second-generation TKIs were evaluated in resistant CML cells K562-R. CPT and imatinib were orally administered once daily for 21 days on K562-R xenografts in nude mice (6 per group). Tumour proliferation and apoptosis were examined by Ki-67, PCNA and TUNEL staining. The expression levels of apoptotic markers and activities of STAT3 and eIF4E pathways were determined via immunohistochemistry staining and western blotting analysis.

Results

CPT significantly enhanced the antiproliferative effects of TKIs, via triggering cleavages of caspase proteins, and inhibiting activities of STAT3 and eIF4E pathways. The administration of CPT and imatinib dramatically inhibited the tumour growth of xenografts and achieved a suppression of 60.2%, which is 2.6-fold higher than that of single imatinib group. Furthermore, CPT and imatinib increased the apoptotic rates and markedly decreased the phosphorylation levels of STAT3 and eIF4E.

Conclusions

Our results demonstrated that CPT could significantly enhance the antileukemia efficacy of TKIs, suggesting the therapeutic potential of CPT to overcome CML resistance.

中文翻译：

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隐丹参酮通过抑制 STAT3 和 eIF4E 信号通路增强 Bcr-Abl 酪氨酸激酶抑制剂在慢性粒细胞白血病中的疗效

摘要

语境

部分慢性粒细胞白血病 (CML) 患者对 Bcr-Abl 酪氨酸激酶抑制剂 (TKI) 产生耐药性，限制了临床应用。先前的结果已经证明隐丹参酮（CPT）和伊马替尼在体外对 CML 细胞凋亡具有协同作用。

客观的

确定CPT和TKIs对耐药CML细胞的抗白血病作用，进一步研究CPT和伊马替尼联合治疗对异种移植模型中肿瘤生长和凋亡的影响，阐明其调控机制。

材料和方法

在耐药 CML 细胞 K562-R 中评估了 CPT 和第二代 TKI 的联合作用。在裸鼠（每组 6 只）的 K562-R 异种移植物上每天口服一次 CPT 和伊马替尼，持续 21 天。通过 Ki-67、PCNA 和 TUNEL 染色检查肿瘤增殖和凋亡。通过免疫组织化学染色和蛋白质印迹分析确定凋亡标志物的表达水平和 STAT3 和 eIF4E 通路的活性。

结果

CPT 通过触发 caspase 蛋白的切割以及抑制 STAT3 和 eIF4E 通路的活性，显着增强了 TKI 的抗增殖作用。CPT和伊马替尼的给药显着抑制了异种移植物的肿瘤生长，达到了60.2%的抑制率，是单一伊马替尼组的2.6倍。此外，CPT 和伊马替尼增加了细胞凋亡率并显着降低了 STAT3 和 eIF4E 的磷酸化水平。

结论

我们的研究结果表明，CPT 可以显着增强 TKI 的抗白血病疗效，表明 CPT 具有克服 CML 耐药性的治疗潜力。