Huang Kaikai, Sun Zhiqiang, Ding Bingjie, Jiang Xuejie, Wang Zhixiang, Zhu Yufeng, Meng Fanyi
Department of Hematology, Shenzhen Hospital, Southern Medical University, Shenzhen, People's Republic of China.
Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
Onco Targets Ther. 2019 Sep 11;12:7477-7488. doi: 10.2147/OTT.S216628. eCollection 2019.
Hedgehog (Hh) signaling is involved in the pathogenesis of tumors. By performing gene chip analysis, we predicted that Hh signaling might regulate multiple downstream pathways in acute myeloid leukemia (AML).
In this study, the potential role of the Hh pathway in refractory AML, and the impact of Hh expression on clinical prognosis were examined. We also investigated the role of the Hh inhibitor NVP-LDE225 in reversing drug resistance of refractory primary AML cells in vitro and the roles of multiple drug-resistant HL60/Adriamycin-resistant cells in vitro and in vivo (in a xenograft mouse model). Finally, we explored the underlying mechanisms.
Hh pathway was highly active in chemotherapy-resistant AML cells; by contrast, activation was less pronounced in chemosensitive cells and non-refractory primary cells. Strong activation of this pathway was associated with higher recurrence rates and poorer relapse-free and overall survival. NVP-LDE225 inhibited MRP1 protein expression, increased intracellular accumulation of Adriamycin, and reversed chemotherapeutic resistance. These effects were likely mediated through inhibition of the IGF-1R/Akt/MRP1 pathway. In the AML xenograft mouse model, NVP-LDE225 plus Adriamycin resulted in marked tumor regression.
These findings suggest that targeting the Hh pathway might be a therapeutic avenue for overcoming MDR resistance and preventing refractory AML.
刺猬信号通路（Hh）参与肿瘤的发病机制。通过基因芯片分析，我们预测Hh信号通路可能调节急性髓系白血病（AML）中的多个下游通路。
在本研究中，检测了Hh通路在难治性AML中的潜在作用以及Hh表达对临床预后的影响。我们还研究了Hh抑制剂NVP-LDE225在体外逆转难治性原发性AML细胞耐药性中的作用，以及多药耐药HL60/阿霉素耐药细胞在体外和体内（异种移植小鼠模型）中的作用。最后，我们探讨了潜在机制。
Hh通路在化疗耐药的AML细胞中高度活跃；相比之下，在化疗敏感细胞和非难治性原代细胞中激活不太明显。该通路的强烈激活与较高的复发率以及较差的无复发生存期和总生存期相关。NVP-LDE225抑制MRP1蛋白表达，增加阿霉素的细胞内蓄积，并逆转化疗耐药性。这些作用可能是通过抑制IGF-1R/Akt/MRP1通路介导的。在AML异种移植小鼠模型中，NVP-LDE225加阿霉素导致肿瘤明显消退。
这些发现表明，靶向Hh通路可能是克服多药耐药性和预防难治性AML的一种治疗途径。
