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Increasing the Radiosensitivity of MCF-7 Cancer Stem Cells Cultivated as Mammospheres to γ- and γ-Neutron Irradiation with Metformin

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Abstract

Cancer stem cells (CSCs) are highly resistant to chemo- and radiotherapy. The aim of this work was to study the effect of metformin on the radiosensitivity of MCF-7 cells cultivated as mammospheres enriched with CSCs. One hour after the addition of metformin at a nontoxic concentration of 0.25 mmol/L, cells of mammospheres were exposed to γ-radiation at a dose of 2 Gy or reactor γ,n-radiation at a dose of 1 Gy. After 24 hours of cultivation, the drug was removed. Six days after irradiation, the total number of cells was calculated by a hemocytometer, then the percentage of CSCs with the CD44+/CD24–/low phenotype was determined, and the number of CSCs in the samples was calculated. The exposure to γ,n-radiation led to a significant decrease in both the total number of cells and CSCs compared with γ-radiation. The combined exposure to metformin and γ- or γ,n-radiation led to a significant decrease in both the total number of cells and CSCs compared with the exposure to γ-or γ,n-radiation only (p < 0.05). Thus, γ,n-radiation is more effective with respect to eliminating the MCF-7 CSCs than γ-radiation. Metformin increases the sensitivity of the MCF-7 CSCs to γ-and γ,n-radiation.

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REFERENCES

  1. Yang, F., Xu, J., Tang, L., and Guan, X., Breast cancer stem cell: the roles and therapeutic implications, Cell Mol. Life Sci., 2017, vol. 74, no. 6, pp. 951–966. https://doi.org/10.1007/s00018-016-2334-7

    Article  CAS  PubMed  Google Scholar 

  2. Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., et al., Prospective identification of tumorigenic breast cancer cells, Proc. Natl. Acad. Sci. U. S. A., 2003, vol. 100, no. 7, pp. 3983–3988. https://doi.org/10.1073/pnas.0530291100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Li, F., Tiede, B., Massagué, J., et al., Beyond tumorigenesis: cancer stem cells in metastasis, Cell Res., 2007, vol. 17, no. 1, pp. 3–14. https://doi.org/10.1038/sj.cr.7310118

    Article  CAS  PubMed  Google Scholar 

  4. Lee, S.Y., Jeong, E.K., Ju, M.K., et al., Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation, Mol. Cancer, 2017, vol. 16, no. 1, p. 10. https://doi.org/10.1186/s12943-016-0577-4

    Article  PubMed  PubMed Central  Google Scholar 

  5. Matchuk, O.N., Zamulaeva, I.A., Selivanova, E.I., et al., Sensitivity of melanoma B16 side population to low- and high-LET radiation, Radiats. Biol., Radioekol., 2012, vol. 52, no. 3, pp. 261–267.

    CAS  Google Scholar 

  6. Storozhuk, Y., Hopmans, S.N., Sanli, T., et al., Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK, Br. J. Cancer, 2013, vol. 108, no. 10, pp. 2021–2032. https://doi.org/10.1038/bjc.2013.187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hirsch, H.A., Iliopoulos, D., Tsichlis, P.N., et al., Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission, Cancer Res., 2009, vol. 69, no. 19, pp. 7507–7511. https://doi.org/10.1158/0008-5472.CAN-09-2994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kalender, A., Selvaraj, A., Kim, S.Y., et al., Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner, Cell Metab., 2010, vol. 11, no. 5, pp. 390–401. https://doi.org/10.1016/j.cmet.2010.03.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pollack, M.N., Insulin, insulin-like growth factors, insulin resistance, and neoplasia, Am. J. Clin. Nutr., 2007, vol. 86, no. 3, pp. s820–s822. https://doi.org/10.1093/ajcn/86.3.820S

    Article  PubMed  Google Scholar 

  10. Arzumanov, S.S., Safronov, V.V., and Strepetov, A., Determination of the dose absorbed in a biological sample under mixed gamma-neutron irradiation, Zh. Tehn. Fiz., 2018, vol. 8, no. 10, pp. 1581–1584.

    Google Scholar 

  11. Shuvatova, V.G., Kuvyrchenkova, A.P., Syomochkina, Yu.P., and Moskaleva, E.Yu., Radiosensitization of tumor stem cells of human breast adenocarcinoma line MCF-7 using niclosamide, Med. Radiol. Radiats. Bezop., 2017, vol. 62, no. 6, pp. 5–11.

    Article  Google Scholar 

  12. Cho, Y.M., Kim, Y.S., Kang, M.J., et al., Long-term recovery of irradiated prostate cancer increases cancer stem cells, Prostate, 2012, vol. 72, no. 16, pp. 1746–1756. https://doi.org/10.1002/pros.22527

    Article  PubMed  PubMed Central  Google Scholar 

  13. Gomez-Casal, R., Bhattacharya, C., Ganesh, N., et al., Non-small cell lung cancer cells survived ionizing radiation treatment display cancer stem cell and epithelial-mesenchymal transition phenotypes, Mol. Cancer, 2013, vol. 12, no. 1, p. 94. https://doi.org/10.1186/1476-4598-12-94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lagadec, C., Vlashi, E., Della, DonnaL., et al., Radiation-induced reprogramming of breast cancer cells, Stem. Cells, 2012, vol. 30, no. 5, pp. 833–844. https://doi.org/10.1002/stem.1058

    Article  CAS  PubMed  Google Scholar 

  15. Pickup, M., Novitskiy, S., and Moses, H.L., The roles of TGFβ in the tumour microenvironment, Nat. Rev. Cancer, 2013, vol. 13, no. 11, pp. 788–799. https://doi.org/10.1038/nrc3603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kim, E.H., Kim, M.S., Cho, C.K., et al., Low and high linear energy transfer radiation sensitization of HCC cells by metformin, J. Radiat. Res., 2014, vol. 55, no. 3, pp. 432–442. https://doi.org/10.1093/jrr/rrt131

    Article  CAS  PubMed  Google Scholar 

  17. Liu, J., Hou, M., Yuan, T., et al., Enhanced cytotoxic effect of low doses of metformin combined with ionizing radiation on hepatoma cells via ATP deprivation and inhibition of DNA repair, Oncol. Rep., 2012, vol. 28, no. 4, pp. 1406–1412. https://doi.org/10.3892/or.2012.1932

    Article  CAS  PubMed  Google Scholar 

  18. Zhang, T., Zhang, L., Zhang, T., et al., Metformin sensitizes prostate cancer cells to radiation through EGFR/p-DNA-PKCS in vitro and in vivo, Radiat. Res., 2014, vol. 181, no. 6, pp. 641–649. https://doi.org/10.1667/RR13561.1

    Article  CAS  PubMed  Google Scholar 

  19. Junttila, M.R. and de Sauvage, F.J., Influence of tumour micro-environment heterogeneity on therapeutic response, Nature, 2013, vol. 501, no. 7467, pp. 346–354. https://doi.org/10.1038/nature12626

    Article  CAS  PubMed  Google Scholar 

  20. Zannella, V.E., Dal, PraA., Muaddi, H., et al., Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response, Clin. Cancer Res., 2013, vol. 19, no. 24, pp. 6741–6750. https://doi.org/10.1158/1078-0432.CCR-13-1787

    Article  CAS  PubMed  Google Scholar 

  21. Dell’Aglio, D.M., Perino, L.J., Kazzi, Z., et al., Acute metformin overdose: examining serum ph, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature, Ann. Emerg. Med., 2009, vol. 54, no. 6, pp. 818–823. https://doi.org/10.1016/j.annemergmed.2009.04.023

    Article  PubMed  Google Scholar 

  22. Lord, S.R., Cheng, W.C., Liu, D., et al., Integrated pharmacodynamic analysis identifies two metabolic adaption pathways to metformin in breast cancer, Cell Metab., 2018, vol. 28, no. 5, pp. 679–688. e4. https://doi.org/10.1016/j.cmet.2018.08.021

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ACKNOWLEDGMENTS

The authors are grateful to the researchers of the Kurchatov Nuclear Physics Complex A.N. Strepetov and Yu.N. Panin for irradiating cell samples at the IR-8 reactor.

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Authors and Affiliations

  1. National Research Center Kurchatov Institute, Moscow, Russia

    V. G. Shuvatova, A. P. Kuvyrchenkova, Yu. P. Semochkina & E. Yu. Moskaleva

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  1. V. G. Shuvatova
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  2. A. P. Kuvyrchenkova
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  3. Yu. P. Semochkina
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  4. E. Yu. Moskaleva
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Correspondence to V. G. Shuvatova.

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The authors declare that they have no conflicts of interest. This article does not contain any studies involving animals or human participants performed by any of the authors.

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Shuvatova, V.G., Kuvyrchenkova, A.P., Semochkina, Y.P. et al. Increasing the Radiosensitivity of MCF-7 Cancer Stem Cells Cultivated as Mammospheres to γ- and γ-Neutron Irradiation with Metformin. Biol Bull Russ Acad Sci 49, 2314–2321 (2022). https://doi.org/10.1134/S1062359022120214

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  • DOI: https://doi.org/10.1134/S1062359022120214

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