Breast cancer organoid model allowed to reveal potentially beneficial combinations of 3,3′-diindolylmethane and chemotherapy drugs

Biochimie. 2020. Vol. 179. P. 217–227.

Nikulin S., Alekseev B. Y., Sergeeva N. S., Karalkin P. A., Nezhurina E. K., Kirsanova V. A., Sviridova I. K., Akhmedova S. A., Volchenko N. N., Bolotina L. V., Osipyants A. I., Hushpulian D. M., Topchiy M. A., Asachenko A. F., Koval A. P., Shcherbo D. S., Kiselev V. I., Mikhaylenko D. S., Schumacher U., Poloznikov A.

Epigenetic alterations represent promising therapeutic targets in cancer treatment. Recently it was revealed that small molecules have the potential to act as microRNA silencers. Capacity to bind the discrete stem-looped structure of pre-miR-21 and prevent its maturation opens opportunities to utilize such compounds for the prevention of initiation, progression, and chemoresistance of cancer. Molecular simulations performed earlier identified 3,3′-diindolylmethane (DIM) as a potent microRNA-21 antagonist. However, data on DIM and microRNA-21 interplay is controversial, which may be caused by the limitations of the cell lines.

In this study, we established a tumor organoid culture from metastatic breast cancer and tested the efficiency of DIM in combination with common chemotherapeutic drugs used in clinic. Organoids shared morphologic features with the primary tumor, captured tumor heterogeneity, and possessed unique genetic characteristics. Here, we report that DIM suppresses mir-21-5p expression and enhances susceptibility of patient-derived breast cancer organoid to cyclophosphamide and methotrexate treatment. Our data support the hypothesis that small molecules can be utilized as microRNA silencers to overcome cancer-related drug resistance and other pathologies.

Keywords: Breast cancer, опухолевые органоиды, Patient-derived organoids, microRNA-21, 3,3′-diindolylmethane, cyclophosphamide, methotrexate, микроРНК-21, 3,3'-дииндолилметан, циклофосфамид, метотрексат