Hexamethylene amiloride synergizes with venetoclax to induce lysosome-dependent cell death in acute myeloid leukemia

Xinya Jiang; Kexiu Huang; Xiaofan Sun; Yue Li; Lei Hua; Fangshu Liu; Rui Huang; Juan Du; Hui Zeng

doi:10.1016/j.isci.2023.108691

Hexamethylene amiloride synergizes with venetoclax to induce lysosome-dependent cell death in acute myeloid leukemia

iScience. 2023 Dec 8;27(1):108691. doi: 10.1016/j.isci.2023.108691. eCollection 2024 Jan 19.

Authors

Xinya Jiang^{1

2}, Kexiu Huang¹, Xiaofan Sun¹, Yue Li¹, Lei Hua¹, Fangshu Liu¹, Rui Huang³, Juan Du¹, Hui Zeng¹

Affiliations

¹ Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China.
² Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
³ Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou, P.R. China.

Abstract

Tumors maintain an alkaline intracellular environment to enable rapid growth. The proton exporter NHE1 participates in maintenance of this pH gradient. However, whether targeting NHE1 could inhibit the growth of tumor cells remains unknown. Here, we report that the NHE1 inhibitor Hexamethylene amiloride (HA) efficiently suppresses the growth of AML cell lines. Moreover, HA combined with venetoclax synergized to efficiently inhibit the growth of AML cells. Interestingly, lysosomes are the main contributors to the synergism of HA and venetoclax in inhibiting AML cells. Most importantly, the combination of HA and venetoclax also had prominent anti-leukemia effects in both xenograft models and bone marrow samples from AML patients. In summary, our results provide evidence that the NHE1 inhibitor HA or its combination with venetoclax efficiently inhibits the growth of AML in vitro and in vivo.

Keywords: Cancer; Cell biology; Cellular toxicology; Molecular medicine.