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Low-dose radiation-induced cell death in doxorubicin-sensitive leukemic K562 and resistant leukemic K562/Dox cancer cells associated with ferroptosis induction

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Abstract

Objective

It has been reported that low-dose total body irradiation techniques can be applied to blood cancers such as leukemia. The aim of this study is to investigate the effect of low-dose radiation-induced cell death via ferroptosis phenomenon in doxorubicin-sensitive leukemic K562 and resistant leukemic K562/Dox cancer cells.

Method

The cells were irradiated with X-rays at total doses of 0, 0.02, 0.05, and 0.1 Gy. The cell viability was determined at 48 h post-irradiation. Other biological endpoints related to ferroptosis included intracellular reactive oxygen species (ROS) that were determined at 5, 10, and 30 min post-irradiation. Also, intracellular iron, lipid peroxidation, and glutathione peroxidase (GSH-Px) were determined at 1, 4, and 24 h post-irradiation.

Results

The results showed that cell viability significantly decreased in irradiated cells when compared to non-irradiated cells. Intracellular ROS, intracellular iron, and lipid peroxidation increased in irradiated cells at all harvest time points compared to non-irradiated cells. GSH-Px decreased in irradiated cells at all harvest time points compared to non-irradiated cells.

Conclusion

These findings suggest that low-dose radiation can induce cell death in doxorubicin-sensitive leukemic K562 and resistant leukemic K562/Dox cancer cells through ferroptosis pathways.

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References

  1. Bray F et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492

    Article  PubMed  Google Scholar 

  2. Gewirtz D (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741. https://doi.org/10.1016/S0006-2952(98)00307-4

    Article  CAS  PubMed  Google Scholar 

  3. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229. https://doi.org/10.1124/pr.56.2.6

    Article  CAS  PubMed  Google Scholar 

  4. Meredith AM, Dass CR (2016) Increasing role of the cancer chemotherapeutic doxorubicin in cellular metabolism. J Pharm Pharmacol 68:729–741. https://doi.org/10.1111/jphp.12539

    Article  CAS  PubMed  Google Scholar 

  5. Michieli M et al (1994) Restoring uptake and retention of daunorubicin and idarubicin in P170-related multidrug resistance cells by low concentration D-verapamil, cyclosporin-A and SDZ PSC 833. Haematologica 79:500–507

    CAS  PubMed  Google Scholar 

  6. Xia Q et al (2012) Reversion of p-glycoprotein-mediated multidrug resistance in human leukemic cell line by diallyl trisulfide. Evid Based Complement Alternat Med 2012:719805. https://doi.org/10.1155/2012/719805

    Article  PubMed  PubMed Central  Google Scholar 

  7. Barrand MA, Bagrij T, Neo SY (1997) Multidrug resistance-associated protein: a protein distinct from P-glycoprotein involved in cytotoxic drug expulsion. Gen Pharmacol 28:639–645. https://doi.org/10.1016/s0306-3623(96)00284-4

    Article  CAS  PubMed  Google Scholar 

  8. Choi CH (2005) ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int 5:30. https://doi.org/10.1186/1475-2867-5-30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang K, Wu J, Li X (2008) Recent advances in the research of P-glycoprotein inhibitors. Biosci Trends 2:137–146

    PubMed  Google Scholar 

  10. Li J et al (2012) A review on various targeted anticancer therapies. Target Oncol 7:69–85. https://doi.org/10.1007/s11523-012-0212-2

    Article  PubMed  Google Scholar 

  11. Delaney G, Jacob S, Featherstone C, Barton M (2005) The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer 104:1129–1137. https://doi.org/10.1002/cncr.21324

    Article  PubMed  Google Scholar 

  12. Morgan MA, Lawrence TS (2015) Molecular pathways: overcoming radiation resistance by targeting DNA damage response pathways. Clin Cancer Res 21:2898–2904. https://doi.org/10.1158/1078-0432.Ccr-13-3229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kim BM et al (2015) Therapeutic implications for overcoming radiation resistance in cancer therapy. Int J Mol Sci 16:26880–26913. https://doi.org/10.3390/ijms161125991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Willers H, Azzoli CG, Santivasi WL, Xia F (2013) Basic mechanisms of therapeutic resistance to radiation and chemotherapy in lung cancer. Cancer J 19:200–207. https://doi.org/10.1097/PPO.0b013e318292e4e3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Goldstein M, Kastan MB (2015) The DNA damage response: implications for tumor responses to radiation and chemotherapy. Annu Rev Med 66:129–143. https://doi.org/10.1146/annurev-med-081313-121208

    Article  CAS  PubMed  Google Scholar 

  16. Chaurasia M, Bhatt AN, Das A, Dwarakanath BS, Sharma K (2016) Radiation-induced autophagy: mechanisms and consequences. Free Radic Res 50:273–290. https://doi.org/10.3109/10715762.2015.1129534

    Article  CAS  PubMed  Google Scholar 

  17. Dixon SJ et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149:1060–1072. https://doi.org/10.1016/j.cell.2012.03.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Stockwell BR et al (2017) Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171:273–285. https://doi.org/10.1016/j.cell.2017.09.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gao M, Jiang X (2018) To eat or not to eat-the metabolic flavor of ferroptosis. Curr Opin Cell Biol 51:58–64. https://doi.org/10.1016/j.ceb.2017.11.001

    Article  CAS  PubMed  Google Scholar 

  20. Yang WS, Stockwell BR (2016) Ferroptosis: death by lipid peroxidation. Trends Cell Biol 26:165–176. https://doi.org/10.1016/j.tcb.2015.10.014

    Article  CAS  PubMed  Google Scholar 

  21. Yang WS et al (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156:317–331. https://doi.org/10.1016/j.cell.2013.12.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang Y et al (2019) Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem Biol 26:623-633.e629. https://doi.org/10.1016/j.chembiol.2019.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nwokocha CR et al (2012) Proteins and liver function changes in rats following cumulative total body irradiations. West Indian Med J 61:773–777

    CAS  PubMed  Google Scholar 

  24. Walch J, Tettenborn B, Weber J, Hundsberger T (2013) Radiation-induced cavernoma after total body irradiation and haematopoietic stem cell transplantation in an adult patient suffering from acute myeloid leukaemia. Case Rep Neurol 5:91–97. https://doi.org/10.1159/000351069

    Article  PubMed  PubMed Central  Google Scholar 

  25. Nomura T, Sakai K, Ogata H, Magae J (2013) Prolongation of life span in the accelerated aging klotho mouse model, by low-dose-rate continuous γ irradiation. Radiat Res 179:717–724. https://doi.org/10.1667/rr2977.1

    Article  CAS  PubMed  Google Scholar 

  26. Supawat B et al (2021) Different responses of normal cells (red blood cells) and cancer cells (K562 and K562/Dox cells) to low-dose <sup>137</sup>Cs gamma-rays. Mol Clin Oncol 14:74. https://doi.org/10.3892/mco.2021.2236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Azzam EI, Jay-Gerin JP, Pain D (2012) Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury. Cancer Lett 327:48–60. https://doi.org/10.1016/j.canlet.2011.12.012

    Article  CAS  PubMed  Google Scholar 

  28. Shadyro OI, Yurkova IL, Kisel MA (2002) Radiation-induced peroxidation and fragmentation of lipids in a model membrane. Int J Radiat Biol 78:211–217. https://doi.org/10.1080/09553000110104065

    Article  CAS  PubMed  Google Scholar 

  29. Lei G et al (2020) The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res 30:146–162. https://doi.org/10.1038/s41422-019-0263-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yin J et al (2021) Identification of ferroptosis biomarker in AHH-1 lymphocytes associated with low dose radiation. Health Phys 120:541–551. https://doi.org/10.1097/hp.0000000000001385

    Article  CAS  PubMed  Google Scholar 

  31. Aye KT et al (2021) Gallic acid enhances pirarubicin-induced anticancer in living K562 and K562/Dox leukemia cancer cells through cellular energetic state impairment and P-glycoprotein inhibition. Oncol Rep 46:227. https://doi.org/10.3892/or.2021.8178

    Article  CAS  PubMed  Google Scholar 

  32. Myint O et al (2021) Protein binding of 4-hydroxybenzoic acid and 4-hydroxy-3-methoxybenzoic acid to human serum albumin and their anti-proliferation on doxorubicin-sensitive and doxorubicin-resistant leukemia cells. Toxicol Rep 8:1381–1388. https://doi.org/10.1016/j.toxrep.2021.07.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Supawat B et al (2020) Effects of gadolinium-based magnetic resonance imaging contrast media on red blood cells and K562 cancer cells. J Trace Elem Med Biol 62:126640. https://doi.org/10.1016/j.jtemb.2020.126640

    Article  CAS  PubMed  Google Scholar 

  34. Supawat B, Udomtanakunchai C, Kothan S, Tungjai M (2019) the effects of iodinated radiographic contrast media on multidrug-resistant K562/Dox cells: mitochondria impairment and P-glycoprotein inhibition. Cell Biochem Biophys 77:157–163. https://doi.org/10.1007/s12013-019-00868-3

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This research was partially supported by Chiang Mai University. This study was also supported by the Faculty of Associated Medical Sciences, Chiang Mai University.

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Correspondence to Montree Tungjai.

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Sakornniya Wattanapongpitak, Suchart Kothan, Singkome Tima, and Montree Tungjai all declare that they have no conflicts of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Wattanapongpitak, S., Kothan, S., Tima, S. et al. Low-dose radiation-induced cell death in doxorubicin-sensitive leukemic K562 and resistant leukemic K562/Dox cancer cells associated with ferroptosis induction. Toxicol. Environ. Health Sci. 15, 249–255 (2023). https://doi.org/10.1007/s13530-023-00178-5

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