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The Effect of DNA-Binding Ligands from Dimeric Bisbenzimidazoles of the DBA(n) and DBPA(n) Series in Combination with γ-Radiation on Epithelial–Mesenchymal Transition and Pool Size of MCF-7 Breast Cancer Stem Cells

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Abstract

Radiation therapy is one of the main methods of treating malignant neoplasms, including breast cancer. However, it is known that it can lead to an increase in the number of cancer stem cells that are resistant to traditional antiегьщк medicines and are believed to be responsible for the development of relapses and metastases. Therefore, the development of means for the elimination of cancer stem cells, especially in combination with ionizing radiation, is of considerable interest. The effects of the single and combined exposure of a new series of minor-groove DNA ligands-dimeric bisbenzimidazoles DBA(n) and DBPA(n) (where n is the number of methylene groups between two bisbenzimidazole blocks) and γ-radiation on human breast cancer cells of the MCF-7 line in vitro were studied. In particular, compounds with the maximum cytotoxic effect and binding to cells were selected; the effect of the latter on the population of CD44+CD24−/low cancer stem cells and radiation-induced epithelial–mesenchymal transition was studied according to the criterion of vimentin expression. An increase in the expression level of this protein and, at the same time, the relative number of cancer stem cells after a single exposure to γ-radiation at a dose of 4 Gy was shown. DBPA(1,4) in combination with irradiation blocked radiation-induced expression of vimentin and reduced the relative number of cancer stem cells by 1.7 and 4.1 times compared with irradiation alone, respectively (p = 0.041 and p = 0.005). At the same time, the absolute number of cancer stem cells decreased by 2.8 and 12.0 times compared to irradiation alone, respectively (p = 0.029 and p = 0.004). The single and combined effect of DBA(5,7) with gamma radiation increased the expression of vimentin; the same compounds, when combined with irradiation, increased the relative number of cancer stem cells by 3.1 and 3.6 times compared with irradiation alone, respectively (p = 0.006 and p = 0.005). The absolute number of cancer stem cells increased by 2.2 and 1.5 times, respectively (p = 0.017 and p = 0.032). The data we obtained demonstrated a close relationship between the process of epithelial–mesenchymal transition and the formation of a pool of cancer stem cells after radiation exposure; they also indicated the prospects for further study of DBPA(1,4) as a means of eliminating cancer stem cells in vivo.

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Funding

The research was carried out with the financial support of the Russian Science Foundation, project no. 18-75-10025.

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Authors and Affiliations

  1. Tsyb Medical Radiological Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, 249031, Obninsk, Kaluga Region, Russia

    K. A. Churiukina, O. N. Matchuk, S. A. Ivanov & I. A. Zamulaeva

  2. Joint Institute for Nuclear Research, 141980, Dubna, Moscow Region, Russia

    O. N. Matchuk & I. A. Zamulaeva

  3. National Medical Research Radiological Center, Ministry of Health of the Russian Federation, 249036, Obninsk, Kaluga oblast, Russia

    A. D. Kaprin

  4. Hertsen Moscow Oncology Research Institute, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, 125284, Moscow, Russia

    A. D. Kaprin

  5. Peoples’ Friendship University of Russia, 117198, Moscow, Russia

    A. D. Kaprin & S. A. Ivanov

  6. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russia

    V. S. Koval, A. F. Arutyunyan & A. L. Zhuze

Authors
  1. K. A. Churiukina
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  2. O. N. Matchuk
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  4. S. A. Ivanov
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  6. A. F. Arutyunyan
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  7. A. L. Zhuze
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  8. I. A. Zamulaeva
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Correspondence to K. A. Churiukina.

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This paper does not describe any studies using humans and animals as objects.

Additional information

Translated by E. Puchkov

Abbreviations: CSCs, tumor stem cells; EMT, epithelial–mesenchymal transition; DB(n), DBA(n), and DBPA(n), dimeric bisbenzimidazoles of various series (dimeric bisbenzimidazoles, where n is the number of methylene groups in the linker); FITC, fluoresceinisothiocyanate; MTT, 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (methyl thiazolyl tetrazolium).

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Churiukina, K.A., Matchuk, O.N., Kaprin, A.D. et al. The Effect of DNA-Binding Ligands from Dimeric Bisbenzimidazoles of the DBA(n) and DBPA(n) Series in Combination with γ-Radiation on Epithelial–Mesenchymal Transition and Pool Size of MCF-7 Breast Cancer Stem Cells. BIOPHYSICS 68, 422–434 (2023). https://doi.org/10.1134/S0006350923030065

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