Effects of DNA-binding ligands from dimeric bisbenzimidazoles series DBA(n) and DBPA( n) in combination with γ-radiation on epithelial-mesenchymal transition and pool size of MCF-7 breast cancer stem cells

Abstract

Radiation therapy is one of the main treatments for malignant neoplasms, including breast cancer. However, it is known, that radiation therapy can lead to an increase in the number of cancer stem cells, which are resistant to traditional antitumor effects, and are believed to be responsible for the development of recurrences and metastases. Therefore, the development of cancer stem cells elimination means is of considerable interest, especially in combination with ionizing radiation. The effects of single and combined exposure to 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 Y-radiation on human Breast cancer cells were studied in our work for MCF-7 line in vitro. Compounds with maximum cytotoxic effect and cell binding were selected, and then the effects of the latter on the CD44+CD24-/low cancer stem cells population and radiation-induced epithelial-mesenchymal transition were studied by the criterion of vimentin expression. An increase in the expression level of this protein and simultaneously in the relative number of cancer stem cells after a single exposure of Y-radiation at a dose of 4 Gy were shown. DBPA(1,4) in combination with irradiation blocked the radiation-induced vimentin expression and decreased the relative number of cancer stem cells by 1.7 and 4.1 times compared with irradiation (p = 0.041 and p = 0.005), respectively. At the same time, the absolute number of cancer stem cells decreased by 2.8 and 12.0 times compared to irradiation (p = 0.029 and p = 0.004), respectively. In contrast, DBA(5,7) by itself or in combination with Y-irradiation increased the level of vimentin expression and the same compounds when combined with irradiation increased the relative number of cancer stem cells by 3.1 and 3.6 times (p = 0.006 and p = 0.005), respectively, compared with irradiation. The absolute number of cancer stem cells increased by 2.2 and 1.5 times (p = 0.017 and p = 0.032), respectively. The data obtained show a close relationship between epithelial-mesenchymal transition and formation of the cancer stem cells pool after radiation exposure, and also indicate the prospects for further study of DBPA(1,4) as a means of cancer stem cells elimination under in vivo conditions.