Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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.

References

  1. Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA. 2010;107:8788–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wise DR, Thompson CB. Glutamine addiction: A new therapeutic target in cancer. Trends Biochem Sci. 2010;35:427–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Battogtokh G, Cho YY, Lee JY, Lee HS, Kang HC. Mitochondrial-targeting anticancer agent conjugates and nanocarrier systems for cancer treatment. Front Pharm. 2018;9:922.

    Article  CAS  Google Scholar 

  4. Neagu M, Constantin C, Popescu ID, Zipeto D, Tzanakakis G, Nikitovic D, et al. Inflammation and metabolism in cancer cell-mitochondria key player. Front Oncol. 2019;9:348.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Macleod K. Mitophagy and mitochondrial dysfunction in cancer. Annu Rev Cancer Biol. 2020;4:41–60.

    Article  Google Scholar 

  6. Moro L. Mitochondrial dysfunction in aging and cancer. J Clin Med. 2019;8:1983.

  7. Zanotto-Filho A, Delgado-Cañedo A, Schröder R, Becker M, Klamt F, Moreira JC. The pharmacological NFkappaB inhibitors BAY117082 and MG132 induce cell arrest and apoptosis in leukemia cells through ROS-mitochondria pathway activation. Cancer Lett. 2010;288:192–203.

    Article  CAS  PubMed  Google Scholar 

  8. Zunino SJ, Storms DH. Resveratrol-induced apoptosis is enhanced in acute lymphoblastic leukemia cells by modulation of the mitochondrial permeability transition pore. Cancer Lett. 2006;240:123–34.

    Article  CAS  PubMed  Google Scholar 

  9. Baccelli I, Gareau Y, Lehnertz B, Gingras S, Spinella JF, Corneau S, et al. Mubritinib targets the electron transport chain complex I and reveals the landscape of OXPHOS dependency in acute myeloid leukemia. Cancer Cell. 2019;36:84–99.e8.

    Article  CAS  PubMed  Google Scholar 

  10. Sillar JR, Germon ZP, DeIuliis GN, Dun MD. The role of reactive oxygen species in acute myeloid leukaemia. Int J Mol Sci. 2019;20:6003.

  11. Kreitz J, Schönfeld C, Seibert M, Stolp V, Alshamleh I, Oellerich T, et al. Metabolic plasticity of acute myeloid leukemia. Cells. 2019;8:805.

  12. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115:453–74.

    Article  PubMed  CAS  Google Scholar 

  13. Panina SB, Baran N, Brasil da Costa FH, Konopleva M, Kirienko NV. A mechanism for increased sensitivity of acute myeloid leukemia to mitotoxic drugs. Cell Death Dis. 2019;10:617.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Panina SB, Pei J, Baran N, Konopleva M, Kirienko NV. Utilizing synergistic potential of mitochondria-targeting drugs for leukemia therapy. Front Oncol. 2020;10:435.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wang Y, Liu HH, Cao YT, Zhang LL, Huang F, Yi C. The role of mitochondrial dynamics and mitophagy in carcinogenesis, metastasis and therapy. Front Cell Dev Biol. 2020;8:413.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Vara-Perez M, Felipe-Abrio B, Agostinis P. Mitophagy in cancer: A tale of adaptation. Cells. 2019;8:493.

  17. Yan C, Li TS. Dual role of mitophagy in cancer drug resistance. Anticancer Res. 2018;38:617–21.

    Article  CAS  PubMed  Google Scholar 

  18. Biel TG, Rao VA. Mitochondrial dysfunction activates lysosomal-dependent mitophagy selectively in cancer cells. Oncotarget 2018;9:995–1011.

    Article  PubMed  Google Scholar 

  19. Morad SAF, MacDougall MR, Abdelmageed N, Kao LP, Feith DJ, Tan SF, et al. Pivotal role of mitophagy in response of acute myelogenous leukemia to a ceramide-tamoxifen-containing drug regimen. Exp Cell Res. 2019;381:256–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tjahjono E, Pei J, Revtovich AV, Liu T-JE, Swadi A, Hancu MC, et al. Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative disease. Sci Rep. 2021;11:17733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Molina JR, Sun Y, Protopopova M, Gera S, Bandi M, Bristow C, et al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat Med. 2018;24:1036–46.

    Article  CAS  PubMed  Google Scholar 

  22. Bostrom B, Erdmann G. Cellular pharmacology of 6-mercaptopurine in acute lymphoblastic leukemia. Am J Pediatr Hematol Oncol. 1993;15:80–6.

    Article  CAS  PubMed  Google Scholar 

  23. Tacar O, Sriamornsak P, Dass CR. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharm. 2013;65:157–70.

    Article  CAS  Google Scholar 

  24. Pei J, Panina SB, Kirienko NV. An automated differential nuclear staining assay for accurate determination of mitocan cytotoxicity. J Vis Exp. 2020;159:e61295.

  25. Ritz C, Baty F, Streibig JC, Gerhard D, Dose-Response Analysis Using R. PLoS One. 2015;10:e0146021.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Ianevski A, He L, Aittokallio T, Tang J. SynergyFinder: a web application for analyzing drug combination dose-response matrix data. Bioinformatics 2017;33:2413–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA, et al. Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem. 2003;278:8516–25.

    Article  CAS  PubMed  Google Scholar 

  28. Chaoui D, Faussat AM, Majdak P, Tang R, Perrot JY, Pasco S, et al. JC-1, a sensitive probe for a simultaneous detection of P-glycoprotein activity and apoptosis in leukemic cells. Cytom B Clin Cytom. 2006;70:189–96.

    Article  CAS  Google Scholar 

  29. Brookes PS. Mitochondrial H(+) leak and ROS generation: an odd couple. Free Radic Biol Med. 2005;38:12–23.

    Article  CAS  PubMed  Google Scholar 

  30. Kari E, Teppo HR, Haapasaari KM, Kuusisto MEL, Lemma A, Karihtala P, et al. Nuclear factor erythroid 2-related factors 1 and 2 are able to define the worst prognosis group among high-risk diffuse large B cell lymphomas treated with R-CHOEP. J Clin Pathol. 2019;72:316–21.

    Article  CAS  PubMed  Google Scholar 

  31. Evans MJ, Scarpulla RC. NRF-1: A trans-activator of nuclear-encoded respiratory genes in animal cells. Genes Dev. 1990;4:1023–34.

    Article  CAS  PubMed  Google Scholar 

  32. Vélez J, Hail N, Konopleva M, Zeng Z, Kojima K, Samudio I, et al. Mitochondrial uncoupling and the reprograming of intermediary metabolism in leukemia cells. Front Oncol. 2013;3:67.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Mookerjee SA, Brand MD. Measurement and analysis of extracellular acid production to determine Glycolytic rate. J Vis Exp. 2015;106:e53464.

    Google Scholar 

  34. Jantas D, Chwastek J, Grygier B, Lasoń W. Neuroprotective effects of Necrostatin-1 against oxidative stress-induced cell damage: An involvement of Cathepsin D inhibition. Neurotox Res. 2020;37:525–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yao X, Zhang Y, Hao J, Duan HQ, Zhao CX, Sun C, et al. Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis. Neural Regen Res. 2019;14:532–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. Blood 2016;127:53–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tamamyan G, Kadia T, Ravandi F, Borthakur G, Cortes J, Jabbour E, et al. Frontline treatment of acute myeloid leukemia in adults. Crit Rev Oncol Hematol. 2017;110:20–34.

    Article  PubMed  Google Scholar 

  39. Han L, Cavazos A, Baran N, Zhang Q, Kuruvilla VM, Gay JP, et al. Mitochondrial Oxphos as survival mechanism of minimal residual AML cells after induction chemotherapy: Survival benefit By Complex I inhibition with Iacs-010759. Blood 2019;134:5161.

    Article  Google Scholar 

  40. Baran N, Lodi A, Sweeney SR, Renu P, Kuruvilla VM, Cavazos A, et al. Mitochondrial complex I inhibitor Iacs-010759 reverses the NOTCH1-driven metabolic reprogramming in T-ALL via blockade of oxidative phosphorylation: Synergy with chemotherapy and glutaminase inhibition. Blood 2018;132:4020.

    Article  Google Scholar 

  41. Rytelewski M, Harutyunyan K, Baran N, Mallampati S, Zal M, Cavazos A, et al. Inhibition of oxidative phosphorylation reverses bone marrow hypoxia visualized in imageable syngeneic B-ALL Mouse Model. Front Oncol. 2020;10:991.

  42. Castelli G, Pelosi E, Testa U. Emerging therapies for acute myelogenus leukemia patients targeting apoptosis and mitochondrial metabolism. Cancers (Basel). 2019;11:260.

  43. Basak NP, Banerjee S. Mitochondrial dependency in progression of acute myeloid leukemia. Mitochondrion 2015;21:41–8.

    Article  CAS  PubMed  Google Scholar 

  44. Filimonov DA, Lagunin AA, Gloriozova TA, Rudik AV, Druzhilovskii DS, Pogodin PV, et al. Prediction of the Biological Activity Spectra of Organic Compounds Using the Pass Online Web Resource. Chem Heterocycl Compd. 2014;50:444–57.

    Article  CAS  Google Scholar 

  45. Bright SA, Byrne AJ, Vandenberghe E, Browne PV, Mcelligott AM, Meegan MJ, et al. Selected nitrostyrene compounds demonstrate potent activity in chronic lymphocytic leukaemia cells, including those with poor prognostic markers. Oncol Rep. 2019;41:3127–36.

    CAS  PubMed  Google Scholar 

  46. Wang YY, Chen YK, Hsu YL, Chiu WC, Tsai CH, Hu SC, et al. Synthetic β-nitrostyrene derivative CYT-Rx20 as inhibitor of oral cancer cell proliferation and tumor growth through glutathione suppression and reactive oxygen species induction. Head Neck. 2017;39:1055–64.

    Article  PubMed  Google Scholar 

  47. Han K, Jeng EE, Hess GT, Morgens DW, Li A, Bassik MC. Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nat Biotechnol. 2017;35:463–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rowe JM. Therapy of secondary leukemia. Leukemia 2002;16:748–50.

    Article  CAS  PubMed  Google Scholar 

  49. Veelken H, Licht T, Lais A, Köhler G, Mertelsmann R, Schaefer HE, et al. Drug resistance of secondary acute myeloid leukemia with megakaryoblastic features and p190 BCR-ABL rearrangement. Leuk Res. 1998;22:1021–7.

    Article  CAS  PubMed  Google Scholar 

  50. Kim EH, Sohn S, Kwon HJ, Kim SU, Kim MJ, Lee SJ, et al. Sodium selenite induces superoxide-mediated mitochondrial damage and subsequent autophagic cell death in malignant glioma cells. Cancer Res. 2007;67:6314–24.

    Article  CAS  PubMed  Google Scholar 

  51. Yan C, Luo L, Guo CY, Goto S, Urata Y, Shao JH, et al. Doxorubicin-induced mitophagy contributes to drug resistance in cancer stem cells from HCT8 human colorectal cancer cells. Cancer Lett. 2017;388:34–42.

    Article  CAS  PubMed  Google Scholar 

  52. Pei S, Minhajuddin M, Adane B, Khan N, Stevens BM, Mack SC, et al. AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells. Cell Stem Cell. 2018;23:86–100.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fay HRS, Dykstra KM, Johnson M, Cronin TL, Lutgen-Dunckley L, Martens BL, et al. Mitophagy Plays a Key Role in the Anti-Leukemic Activity of Autophagy Inhibitors Under Hypoxia in Acute Myeloid Leukemia. Blood 2019;134:1278.

    Article  Google Scholar 

  54. Abo Elwafa R, Gamaleldin M, Ghallab O. The clinical and prognostic significance of FIS1, SPI1, PDCD7 and Ang2 expression levels in acute myeloid leukemia. Cancer Genet. 2019;233-234:84–95.

    Article  CAS  PubMed  Google Scholar 

  55. Dany M, Gencer S, Nganga R, Thomas RJ, Oleinik N, Baron KD, et al. Targeting FLT3-ITD signaling mediates ceramide-dependent mitophagy and attenuates drug resistance in AML. Blood 2016;128:1944–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: Review of current knowledge and evidence. Leukemia 2019;33:299–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yao N, Wang C, Hu N, Li Y, Liu M, Lei Y, et al. Inhibition of PINK1/Parkin-dependent mitophagy sensitizes multidrug-resistant cancer cells to B5G1, a new betulinic acid analog. Cell Death Dis. 2019;10:232.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Kameyama K, Motoyama K, Tanaka N, Yamashita Y, Higashi T, Arima H. Induction of mitophagy-mediated antitumor activity with folate-appended methyl-β-cyclodextrin. Int J Nanomed. 2017;12:3433–46.

    Article  CAS  Google Scholar 

  59. Basit F, van Oppen LM, Schöckel L, Bossenbroek HM, van Emst-de Vries SE, Hermeling JC, et al. Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. Cell Death Dis. 2017;8:e2716.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

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).

Author information

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

Authors
  1. Svetlana B. Panina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingqi Pei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Natalia Baran
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elissa Tjahjono
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shraddha Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gheath Alatrash
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sergej Konoplev
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Leonid A. Stolbov
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vladimir V. Poroikov
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marina Konopleva
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Natalia V. Kirienko
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Natalia V. Kirienko.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-022-01614-0

Search

Advanced search

Quick links