Antiproliferative activity of the novel CYP17A1 inhibitor alsevirone

Abstract

BACKGROUND: Prostate cancer is the most frequently diagnosed type of cancer in men in developed countries. It is dependent upon androgens and could be effectively combated by androgen deprivation therapy. Reduction of androgen synthesis can be accomplished through the inhibition of the enzyme 17α-hydroxylase/17.20-lyase (CYP17A1), which catalyzes two sequential reactions in the production of androgens. Steroid derivatives modified with nitrogen-containing heterocycles attract attention as antineoplastic agents for prostate cancer treatment due to their inhibitory potential against CYP17A1.

AIM: Evaluate cytotoxic activity and antitumor effects of the synthesized alsevirone in comparison with abiraterone.

METHODS: Cytotoxicity was evaluated using MTT test. Anticancer effect was researched in vivo in prostate cancer xenograft models 22Rv1 and DU145 in Balb/c nude mice. Testosterone concentration was determined using an enzyme-linked immunosorbent assay in blood serum of BDF1 mice.

RESULTS: Alsevirone demonstrated cytotoxic activity in prostate cancer cells: DU145 (23.8±1.2 µM vs 151.4±23.7 µM for abiraterone), 22Rv1 (35.9±5.6 µM vs 109.9±35.2 µM for abiraterone) and LNCaP (22.9±0.5 µM vs 28.8±1.6 µM for abiraterone). Testosterone concentration in blood serum of BDF1 mice reduced by 80% after 10-day treatment. Inhibition of the tumors’ growth in 22Rv1 xenograft model was statistically significant when using alsevirone in comparison with the control group: average tumor volume was 171.6±50.1 mm3 (р=0.022) vs 424.2±70.3 mm3 in control, with tumor growth inhibition index of 59%.

CONCLUSIONS: Alsevirone has a higher cytotoxic potential against prostate cancer cells (DU145, LNCaP and 22Rv1) compared to abiraterone. Alsevirone demonstrated the ability to reduce the concentration of testosterone in the blood serum of BDF1 mice, and statistically significant antitumor activity in 22Rv1 xenograft models.

Keywords

prostate cancer / cell line / CYP17A1 inhibitor / resistance to anticancer agent

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Funding

Государственное задание Министерства науки и высшего образования РФState assignment of the Ministry of Science and Higher Education of the Russian Federation(075-01551-23-00 (FSSF-2023-0006))

Программа фундаментальных научных исследований в РФProgram of fundamental scientific research in the Russian Federation(122030100170-5)

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