Evaluation of cytotoxicity and pro-apoptotic effects of new CYP17A1 inhibitors

Автор: Khan I.I., Aidosov Ch.M., Krivchenko V.O., Latysheva A.S., Zolottsev V.A., Misharin A.Yu., Pokrovsky V.S.

Журнал: Cardiometry @cardiometry

Статья в выпуске: 24, 2022 года.

Бесплатный доступ

The CYP17A1 inhibitors are used to treat castration-resistant prostate cancer. However, the existing shortcomings (side effects and low bio-availability) make the search, synthesis, and evaluation of the biological properties of new agents relevant. The aim of our research work was to investigate the cytotoxic and proapoptotic properties of new compounds: alsevirone and LA-91.

Короткий адрес: https://sciup.org/148326311

IDR: 148326311   |   DOI: 10.18137/cardiometry.2022.24.conf.19

Текст статьи Evaluation of cytotoxicity and pro-apoptotic effects of new CYP17A1 inhibitors

1 – Federal State Autonomous Educational Institution of Higher Education “RUDN”, Moscow, 2 – Federal State Budgetary Institution “National Medical Research Center of Oncology named after N.N. Blokhin” of the Ministry of Health of Russia, Moscow, 3 – Federal State Autonomous Educational Institution of Higher Education “Moscow Institute of Physics and Technology”, Moscow, 4 - Scientific Research Institute of Biomedical Chemistry named after V.N. Orekhovich, Moscow, Russia

The CYP17A1 inhibitors are used to treat castration-resistant prostate cancer. However, the existing shortcomings (side effects and low bio-availability) make the search, synthesis, and evaluation of the biological properties of new agents relevant.

The aim of our research work was to investigate the cytotoxic and proapoptotic properties of new compounds: alsevirone and LA-91.

Results . All studied agents contributed to the inhibition of the enzymatic activity of CYP17A1, whereas at a concentration of 5 / M the most active compound was LA-91, and the amount of androstenedione produced was 2 ± 0.5% compared with the reference (15 ± 3% of the reference after incubation with alsevirone, and 17±3% of the reference with abiraterone). Compound LA-91 was more cytotoxic than abiraterone in all cell cultures, and the IC50 values were recorded as follows: 5.4±1.8 / M (DU-145), 2.6±0.4 / M (22Rv1), 3.7 ±0.6 / M (LNCaP), 2.3±0.6 / M (PC-3). Alsevirone demonstrated its cytotoxic activity comparable to that of abiraterone. It is interesting to note that alsevirone at a dose of 0.3 / M increased the content of phosphorylated histone H2A.X (H2A.X cells (+)) by 1410% of the reference value, while after the incubation with a toxic dose of LA-91, the level of the cells, containing H2A .X (+), reached 92.5%, and that after the use of abiraterone was 53.3% of the reference value. Alsevirone stimulated apoptosis and was accompanied by the caspase 3/7 activation comparable to that of abiraterone. So, 0.06 / M of alsevirone induced an increase in the number of cells with activated caspases 3 and 7 to a level of 286% of the reference, as compared to the same amount of abiraterone with 196% of the reference. Alsevirone also contributed to a significant increase in the expression of the phosphorylated form of Bcl-2 to a level of 352% of the reference compared to 181% of the reference value after the incubation with abiraterone at a dose of 0.3 / M.

Conclusions . Thus, the new inhibitors CYP17A1 successfully decrease the enzymatic activity to a degree comparable to that by made abiraterone. The cytotoxicity of LA-91 is higher than that of alsevirone and abiraterone. Alsevirone promotes the apoptotic cell death, and its mechanism of action differs from that of LA-91 and abiraterone, and it is associated with double-strand breaks in the DNA molecule.

Список литературы Evaluation of cytotoxicity and pro-apoptotic effects of new CYP17A1 inhibitors

  • Kostin V.A., et al. Oxazolinyl derivatives of [17(20)E]-21-norpregnene differing in the structure of A and B rings. Facile synthesis and inhibition of CYP17A1 catalytic activity. Steroids. 2016; 115: 114-122.
Статья