In:
Archiv der Pharmazie, Wiley, Vol. 355, No. 1 ( 2022-01)
Abstract:
The aim of this study was to explore the mechanisms of action of alsevirone in prostate cancer (PC) in vitro and in vivo: CYP17A1 inhibition, cytotoxic, apoptotic, and antitumor effects in comparison with abiraterone. The CYP17A1‐inhibitory activity was investigated in rat testicular microsomes using high‐performance liquid chromatography. Testosterone levels were evaluated using enzyme‐linked immunoassay. IC 50 values were calculated for PC3, DU‐145, LNCaP, and 22Rv1 cells using the MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) test. The antitumor effect in vivo was studied in DU‐145 and 22Rv1 subcutaneous xenografts in Balb/c nude mice. Alsevirone reduced the CYP17A1‐inhibitory activity by 98% ± 0.2%. A statistically significant reduction in the testosterone concentration in murine blood was recorded after the 7th administration of 300 mg/kg alsevirone at 0.31 ± 0.03 ng/ml ( p 〈 .001) versus 0.98 ± 0.22 ng/ml ( p = .392) after abiraterone administration and 1.52 ± 0.49 ng/ml in control animals. Alsevirone was more cytotoxic than abiraterone in DU‐145, LNCaP, and 22Rv1 cells, with IC 50 values of 23.80 ± 1.18 versus 151.43 ± 23.70 μM, 22.87 ± 0.54 versus 28.80 ± 1.61 μM, and 35.86 ± 5.63 versus 109.87 ± 35.15 μM, respectively. Alsevirone and abiraterone significantly increased annexin V‐positive, caspase 3/7‐positive, and activated Bcl‐2‐positive cells. In 22Rv1 xenografts, alsevirone 300 mg/kg × 10/24 h per os inhibited tumor growth: on Day 9 of treatment, tumor growth inhibition = 59% ( p = .022). Thus, alsevirone demonstrated significant antitumor activity associated with CYP17A1 inhibition, apoptosis in PC cells, and testosterone reduction.
Type of Medium:
Online Resource
ISSN:
0365-6233
,
1521-4184
DOI:
10.1002/ardp.202100316
Language:
English
Publisher:
Wiley
Publication Date:
2022
detail.hit.zdb_id:
1496815-0
SSG:
15,3
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