Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro.

Authors

Katie H Hurrish
Yongwei Su
Shraddha Patel
Cassandra L Ramage
Jianlei Zhao
Brianna R Temby
Jenna L Carter
Holly Edwards
Steven A Buck
Sandra E Wiley
Maik Hüttemann
Lisa Polin
Juiwanna Kushner
Sijana H Dzinic
Kathryn White
Xun Bao
Jing Li
Jay Yang
Julie Boerner
Zhanjun Hou
Gheath Al-Atrash
Sergej N Konoplev
Jonathan Busquets
Stefano Tiziani
Larry H Matherly
Jeffrey W Taub
Marina Konopleva
Yubin Ge
Natalia Baran

Publication Date

2-1-2024

Abstract

Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 enhanced VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, a purine biosynthesis inhibitor, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired AraC resistance showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. In vivo studies revealed significantly prolonged survival upon combination therapy of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia compared to the vehicle control. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.

Keywords

Humans, Animals, Mice, Oxidative Phosphorylation, Leukemia, Myeloid, Acute, Bridged Bicyclo Compounds, Heterocyclic, Isoflavones, Purines, Antineoplastic Combined Chemotherapy Protocols, Sulfonamides, Acute myeloid leukemia, ME-344, oxidative phosphorylation, purine biosynthesis, venetoclax

DOI

10.1016/j.bcp.2023.115981

PMID

38081370

PMCID

PMC11149698

PubMedCentral® Posted Date

2-1-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes