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Metal chelator TPEN selectively induces apoptosis in K562 cells through reactive oxygen species signaling mechanism: implications for chronic myeloid leukemia

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Abstract

Chronic myeloid leukemia (CML) is a hematologic disorder characterized by the constitutive expression of BCR-ABL tyrosine kinase. Although successful implementation of tyrosine kinase inhibitors for the treatment of CML remain a traditional choice for molecularly targeted therapy, some patients present primary or secondary resistance to such therapy. Therefore, alternative therapeutic strategies are required to treat resistant CML cells. Accordingly, new anti-proliferative and/or pro-apoptotic compounds would be needed for clinical treatment. In the present investigation, we demonstrate that TPEN (e.g. 3 μM), a lipid-soluble metal chelator, induces apoptosis in K562 cells via a molecular cascade involving H2O2 ≫ JNK, NF-κB > c-JUN, P73 > PUMA, BAX > loss of ΔΨm > CASPASE-3 > nuclei/DNA fragmentation. Fragmentation of the nuclei and DNA are indicative of cell death by apoptosis. Remarkably, the antioxidant N-acetyl-cysteine, and inhibitors of the transcription factors CASPASE 3 and (JNK) kinase, decreased oxidative stress (OS) and cell death in these cells. This is evidenced by fluorescence microscopy, flow cytometry and immunocytochemistry for OS markers (e.g. generation of H2O2 and DJ 1 oxidation) and nuclear expression of apoptotic markers (e.g. activated caspase 3 and JNK kinase). In addition, TPEN causes no detectable damage in human peripheral blood lymphocyte cells (hPBLCs). We conclude that TPEN selectively induces apoptosis in K562 cells via an OS-mechanism. Our findings may provide insight into more effective CML anticancer therapies.

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Acknowledgments

This work was supported by the “Committee for Development and Research [Comite para el Desarrollo y la Investigacion]-CODI”, UdeA, Grants #2013-2570 held by Marlene Jimenez-Del-Rio and Carlos Velez-Pardo. Luisa Rojas-Valencia is a master student from the Neurosciences program at the Basic Biomedical Sciences Academic Corporation, UdeA.

Conflict of interest

The authors declare no conflict of interest.

Author contributions

MJ-Del-R and CV-P conceived and designed the experiments; LMRV performed the experiments; and LMR-V, CV-P, MJ-Del-R analyzed the data; MJ-Del-R contributed reagents/materials/analysis tools; CV-P and MJ-Del-R wrote the paper.

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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, Medellin, Colombia

    Luisa Rojas-Valencia, Carlos Velez-Pardo & Marlene Jimenez-Del-Rio

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  1. Luisa Rojas-Valencia
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  2. Carlos Velez-Pardo
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  3. Marlene Jimenez-Del-Rio
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Correspondence to Carlos Velez-Pardo or Marlene Jimenez-Del-Rio.

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Carlos Velez-Pardo and Marlene Jimenez-Del-Rio share senior authorship.

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Rojas-Valencia, L., Velez-Pardo, C. & Jimenez-Del-Rio, M. Metal chelator TPEN selectively induces apoptosis in K562 cells through reactive oxygen species signaling mechanism: implications for chronic myeloid leukemia. Biometals 30, 405–421 (2017). https://doi.org/10.1007/s10534-017-0015-0

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