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ACUTE MYELOID LEUKEMIA

Novel mitochondria-targeting compounds selectively kill human leukemia cells

Leukemia volume 36, pages 2009–2021 (2022)Cite this article

Subjects

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.

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Fig. 1: Parental PINK-1 stabilizing (PS) compounds and their analogs as potential anti-AML agents.
Fig. 2: Mitochondria-related mechanistic effects of PS hit compounds on cancer and normal blood cells.
Fig. 3: Mitochondrial respiration in leukemic cells is selectively inhibited by PS leads.
Fig. 4: PS molecules induce different cell death pathways.
Fig. 5: PS compounds induced synergistic cytotoxicity when combined with other anti-cancer drugs in AML cell lines and primary AML samples.
Fig. 6: Flow cytometry evaluation of viable cell number and apoptosis induction in primary AML samples and healthy bone marrow cells.
Fig. 7: Preclinical in vivo efficacy of PS127B and PS127E in MOLM14/GFP/LUC xenograft model.

Data availability

The data in this study that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

The code that supports the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The study was supported by the CPRIT grant RR150044 and NIH NIGMS grant R35GM129294 to NVK and NIH NCI grants R01CA231364 and P50 CA100632 to MK. Computer-aided estimation of which regions of the chemical scaffold are relevant for cytotoxicity (L.A.S. and V.V.P.) was performed in the framework of the Russian Federation Fundamental Research Program for the long-term period for 2021–2030 (No. 122030100170-5).

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Author notes

  1. These authors contributed equally: Svetlana B. Panina, Jingqi Pei, Natalia Baran.

Authors and Affiliations

  1. Department of BioSciences, Rice University, Houston, TX, USA

    Svetlana B. Panina, Jingqi Pei, Elissa Tjahjono & Natalia V. Kirienko

  2. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Natalia Baran, Shraddha Patel & Marina Konopleva

  3. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Gheath Alatrash

  4. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sergej Konoplev

  5. Institute of Biomedical Chemistry, Moscow, Russia

    Leonid A. Stolbov & Vladimir V. Poroikov

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  1. Svetlana B. Panina
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Contributions

SBP and JP performed the majority of the experiments and wrote the first draft of the manuscript. NB assisted with ATP measurements, conducted seahorse experiments, flow cytometry experiments, mouse studies, and contributed to manuscript writing and editing. ET performed some of the experiments and contributed to manuscript writing and editing. SP assisted with mouse experiments and provided patient samples, GA, and SNK provided healthy bone marrow and patient samples. LAS and VVP performed cheminformatic analysis. MK and NK performed overall design of the study, acquired funding, and contributed to data analysis and manuscript writing and editing. All authors reviewed the manuscript before submission.

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Correspondence to Natalia V. Kirienko.

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Panina, S.B., Pei, J., Baran, N. et al. Novel mitochondria-targeting compounds selectively kill human leukemia cells. Leukemia 36, 2009–2021 (2022). https://doi.org/10.1038/s41375-022-01614-0

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