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Combinational treatment of TPEN and TPGS induces apoptosis in acute lymphoblastic and chronic myeloid leukemia cells in vitro and ex vivo

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Abstract

TPEN and TPGS have recently shown selective cytotoxic effects in vitro and ex vivo leukemia cells. In this study, we aimed to test the synergistic effect of combined TPEN and TPGS agents (thereafter, T2 combo) on Jurkat (clone-E61), K562, Ba/F3, and non-leukemia peripheral blood lymphocytes (PBL). The ED50 doses (i.e., TPEN ED50: 3.2 μM and TPGS ED50: 34 μM, potency ratio R = 10.62 = TPGS (ED50)/TPEN (ED50)) were identified as dose–effect curve (%DNA fragmentation (sub-G1 phase) versus agent concentration). The most effective synergistic doses were determined according to isobole analysis. The apoptotic and oxidative stress effects of combined doses (TPEN 0.1, 0.5, 1 μM) and TPGS (5, 10, 20 μM)) were evaluated by DNA fragmentation (sub-G1 phase), mitochondrial membrane potential, oxidation of stress sensor protein DJ-1, and activation of executer protein CASPASE-3. They testified to the synergistic effect of the T2 combo (e.g., TPEN 1: TPGS 20, combination index (CI) 0.90 < 1; 1/3.2+ 20/34, > 90% induced apoptosis) in all 3 cell lines. As proof of principle, we challenged complete bone marrow (n = 5) or isolated cells from bone marrow (n = 3) samples from acute pediatric acute B-cell patients and found that T2 combo (1:20; 10:200) dramatically reduced (− 50%) the CD34+/CD19+cell population and increased significantly CD19+/CASP-3+ positive B-ALL cells up to 960%. The T2 combo neither induced DNA fragmentation, altered ΔΨm, nor induced oxidation of stress sensor protein DJ-1, nor activated CASP-3 in PBL cells. We conclude that by using different combinations of TPEN and TPGS, a more efficient treatment strategy can be developed for leukemia patients.

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Acknowledgements

We greatly acknowledge pediatric patients for donating ex vivo B-ALL, and control samples (Table 2) and special thanks to JE Fox (MD) for clinical characterization of patient samples at Children’s Hospital Universitario San Vicente Fundación.

Funding

This study was funded by “Fundacion Alfonso Moreno Jaramillo” Grant #2020-31631 to CV-P. The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), SIU, Calle 70 No. 52-21, and Calle 62 # 52-59, Building 1, Room 412, Medellín, Colombia

    Miguel Mendivil-Perez, Marlene Jimenez-Del-Rio & Carlos Velez-Pardo

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  1. Miguel Mendivil-Perez
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  2. Marlene Jimenez-Del-Rio
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Contributions

Conceptualization: MJ-D-R, CV-P; Formal analysis: MM-P; Investigation: MM-P, MJ-D-R, CV-P; Methodology: MM-P; Project administration: MJ-D-R, CV-P; Resources: CV-P; Supervision: MJ-D-R, CV-P; Visualization: MM-P; Writing—original draft: MJ-D-R, CV-P; Writing—review and editing: MM-P, MJ-D-R, CV-P.

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Correspondence to Marlene Jimenez-Del-Rio or Carlos Velez-Pardo.

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All procedures performed in studies involving human participants were following the ethical standards of the Ethics Committee for Research Act # 04-2018 from Children’s Hospital Universitario San Vicente Fundación and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from pediatric ex vivo B-ALL and control cells collected in the study.

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Consent for publication was obtained from pediatric ex vivo B-ALL and control cells collected in the study.

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Mendivil-Perez, M., Jimenez-Del-Rio, M. & Velez-Pardo, C. Combinational treatment of TPEN and TPGS induces apoptosis in acute lymphoblastic and chronic myeloid leukemia cells in vitro and ex vivo. Med Oncol 39, 109 (2022). https://doi.org/10.1007/s12032-022-01697-w

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