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Kaempferol sensitizes tumor necrosis factor-related apoptosis-inducing ligand-resistance chronic myelogenous leukemia cells to apoptosis

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Abstract

Background

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand, TRAIL, an apoptosis-inducing cytokine, has attracted much attention in the treatment of cancer for its selective toxicity to malignant rather than normal cells. However, the apoptosis-inducing ability of TRAIL is weaker than expected primarily due to cancer cell resistance. As one of the dietary flavonoids, kaempferol, has been shown to be antiproliferative and might have a protective effect against TRAIL resistance, particularly for hematologic malignancies.

Methods and results

Here, we studied the potential of kaempferol to enhance the TRAIL-induced cytotoxicity and apoptosis in human chronic myelogenous leukemia (CML) cell line K-562, as well as the expression of specific genes with impact on TRAIL signal regulation. Analysis of flowcytometry data showed that treatment with kaempferol did enhance sensitivity of CML cells to pro-apoptotic effects of anti-TRAIL antibody. Although the gene expression levels were heterogeneous, cFLIP, cIAP1 and cIAP2 expression were generally downregulated where co-treatment of kaempferol and TRAIL was employed and these effects appeared to be dose-dependent. We further demonstrated that the expression of death receptors 4 and 5 tended to increase subsequent to the combination treatment.

Conclusions

Consequently, it is reasonable to conclude that sensitization of chronic leukemia cells to TRAIL by kaempferol in vitro should be considered as a way of focusing clinical attention on leukemia therapy.

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Data availability

The data presented in this study are available on request from the corresponding author.

Code availability

Not applicable.

Abbreviations

TRAIL:

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand

CML:

Chronic myelogenous leukemia

cFLIP:

Cellular FLICE-like protein

cIAP1:

Cellular inhibitor of apoptosis protein 1

IFN-α:

Interferon‐alpha

DMSO:

Dimethyl sulfoxide

MTT:

3-(4,5-Dimethythaizol-2-yl)-2,5-diphenyltetrazolium bromide

FBS:

Fetal bovine serum

PBS:

Phosphate-buffered saline

NFκB:

Nuclear factor kappa B

XIAP:

X-chromosome-linked IAP

DR4:

Death receptor 4

DR5:

Death receptor 5

PS:

Phosphatidylserine

ERK:

Extracellular signal-regulated kinases

JNK:

1/2, Jun N-terminal kinase

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Acknowledgements

The authors would like to thank the Immunology Research Center (IRC), Tabriz University of Medical Sciences for the financial support of this project.

Funding

This work was supported by the Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran [Grant No. 57664].

Author information

Authors and Affiliations

  1. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Raedeh Saraei, Ali Hassanzadeh & Saeed Solali

  2. Division of Hematology, Faculty of Medicine, Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran

    Raedeh Saraei, Ali Hassanzadeh & Saeed Solali

  3. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Raedeh Saraei

  4. College of Medicine, University of Sulaimani, Sulaimaniyah, Iraq

    Heshu Sulaiman Rahman

  5. Department of Medical Laboratory Sciences, Komar University of Science and Technology, Chaq-Chaq Qularaise, Sulaimaniyah, Iraq

    Heshu Sulaiman Rahman

  6. Hematology Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Masoud Soleimani

  7. Department of Statistics and Epidemiology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

    Mohammad Asghari-Jafarabadi

  8. Center for the Development of Interdisciplinary Research in Islamic Sciences and Heath Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

    Mohammad Asghari-Jafarabadi

  9. Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran

    Adel Naimi

  10. Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Saeed Solali

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  1. Raedeh Saraei
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Contributions

Conceptualization: SS, RS; Methodology: RS, AN, and AH; Writing—original draft preparation: RS; Writing—review and editing: SS, and MS; data analysis: MAJ.

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Correspondence to Saeed Solali.

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Saraei, R., Rahman, H.S., Soleimani, M. et al. Kaempferol sensitizes tumor necrosis factor-related apoptosis-inducing ligand-resistance chronic myelogenous leukemia cells to apoptosis. Mol Biol Rep 49, 19–29 (2022). https://doi.org/10.1007/s11033-021-06778-z

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  • DOI: https://doi.org/10.1007/s11033-021-06778-z

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