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Suppressing Hedgehog signaling reverses drug resistance of refractory acute myeloid leukemia

Authors Huang K, Sun Z, Ding B, Jiang X, Wang Z, Zhu Y, Meng F

Received 22 May 2019

Accepted for publication 16 August 2019

Published 11 September 2019 Volume 2019:12 Pages 7477—7488

DOI https://doi.org/10.2147/OTT.S216628

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Ms Shreya Arora

Peer reviewer comments 2

Editor who approved publication: Dr William Cho


Kaikai Huang,1–3 Zhiqiang Sun,1 Bingjie Ding,2,4 Xuejie Jiang,2 Zhixiang Wang,2 Yufeng Zhu,2 Fanyi Meng2

1Department of Hematology, Shenzhen Hospital, Southern Medical University, Shenzhen, People’s Republic of China; 2Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 4Department of Hematology, Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China

Correspondence: Fanyi Meng
Department of Hematology, Kanghua Hospital, Dongguan 523080, Guangdong, People’s Republic of China
Email mengfu@medmail.com.cn

Background: 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).
Methods: 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.
Results: 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.
Conclusion: These findings suggest that targeting the Hh pathway might be a therapeutic avenue for overcoming MDR resistance and preventing refractory AML.

Keywords: Hedgehog pathway, drug resistance, acute myeloid leukemia
 

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