Novel Mitochondria-Targeting Compounds Selectively Kill Human Leukemia Cells

Authors

Svetlana B Panina
Jingqi Pei
Natalia Baran
Elissa Tjahjono
Shraddha Patel
Gheath Alatrash
Sergej Konoplev
Leonid A Stolbov
Vladimir V Poroikov
Marina Konopleva
Natalia V Kirienko

Publication Date

8-1-2022

Journal

Leukemia

DOI

10.1038/s41375-022-01614-0

PMID

35672446

PMCID

PMC11088873

PubMedCentral® Posted Date

5-12-2024

PubMedCentral® Full Text Version

Author MSS

Abstract

Acute myeloid leukemia (AML) is a heterogeneous group of aggressive hematological malignancies commonly associated with treatment resistance, high risk of relapse, and mitochondrial dysregulation. We identified six mitochondria-affecting compounds (PS compounds) that exhibit selective cytotoxicity against AML cells in vitro. Structure-activity relationship studies identified six analogs from two original scaffolds that had over an order of magnitude difference between LD50 in AML and healthy peripheral blood mononuclear cells. Mechanistically, all hit compounds reduced ATP and selectively impaired both basal and ATP-linked oxygen consumption in leukemic cells. Compounds derived from PS127 significantly upregulated production of reactive oxygen species (ROS) in AML cells and triggered ferroptotic, necroptotic, and/or apoptotic cell death in AML cell lines and refractory/relapsed AML primary samples. These compounds exhibited synergy with several anti-leukemia agents in AML, acute lymphoblastic leukemia (ALL), or chronic myelogenous leukemia (CML). Pilot in vivo efficacy studies indicate anti-leukemic efficacy in a MOLM14/GFP/LUC xenograft model, including extended survival in mice injected with leukemic cells pre-treated with PS127B or PS127E and in mice treated with PS127E at a dose of 5 mg/kg. These compounds are promising leads for development of future combinatorial therapeutic approaches for mitochondria-driven hematologic malignancies such as AML, ALL, and CML.

Keywords

Adenosine Triphosphate, Animals, Hematologic Neoplasms, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Leukemia, Myeloid, Acute, Leukocytes, Mononuclear, Mice, Mitochondria

Published Open-Access

yes

Recommended Citation

Panina, Svetlana B; Pei, Jingqi; Baran, Natalia; et al., "Novel Mitochondria-Targeting Compounds Selectively Kill Human Leukemia Cells" (2022). Faculty, Staff and Student Publications. 4206.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4206