Bcl-2 Inhibition Combined With PPARα Activation Synergistically Targets Leukemic Stem Cell-Like Cells in Acute Myeloid Leukemia

Authors

Chendi Xie
Hui Zhou
Dongmei Qin
Huijian Zheng
Yuanfang Tang
Wenjuan Li
Jie Zhou
Long Liu
Xinxin Yu
Hongpeng Duan
Yong Zhou
Zhifeng Li
Zhihong Fang
Yiming Luo
Bing Z Carter
Bing Xu
Jie Zha

Publication Date

8-29-2023

Journal

Cell Death & Disease

Abstract

Persistence of leukemic stem cells (LSCs) is one of the determining factors to acute myeloid leukemia (AML) treatment failure and responsible for the poor prognosis of the disease. Hence, novel therapeutic strategies that target LSCs are crucial for treatment success. We investigated if targeting Bcl-2 and peroxisome proliferator activated receptor α (PPARα), two distinct cell survival regulating mechanisms could eliminate LSCs. This study demonstrate that the Bcl-2 inhibitor venetoclax combined with the PPARα agonist chiglitazar resulted in synergistic killing of LSC-like cell lines and CD34+ primary AML cells while sparing their normal counterparts. Furthermore, the combination regimen significantly suppressed AML progression in patient-derived xenograft (PDX) mouse models. Mechanistically, chiglitazar-mediated PPARα activation inhibited the transcriptional activity of the PIK3AP1 gene promoter and down-regulated the PI3K/Akt signaling pathway and anti-apoptotic Bcl-2 proteins, leading to cell proliferation inhibition and apoptosis induction, which was synergized with venetoclax. These findings suggest that combinatorial Bcl-2 inhibition and PPARα activation selectively eliminates AML cells in vivo and vitro, representing an effective therapy for patients with relapsed and refractory AML.

Keywords

Humans, Animals, Mice, PPAR alpha, Phosphatidylinositol 3-Kinases, Disease Models, Animal, Stem Cells, Acute myeloid leukaemia, Apoptosis

Comments

Associated Data

PMID: 37644011