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

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.

• Authors: Xinya Jiang, Kexiu Huang, Xiaofan Sun, Yue Li, Lei Hua, Fangshu Liu, Rui Huang, Juan Du, Hui Zeng
• Journal: iScience (iScience) Vol. 27 Issue 1 Pg. 108691 (Jan 19 2024) ISSN: 2589-0042 [Electronic] United States
• PMID: 38205254 (Publication Type: Journal Article)
• Copyright: © 2023 The Authors.