Abstract

Background: The goal of this study was to evaluate the anticancer and testosteroneinhibitory effects of 2‘-{[(E) androst-5-en-17-ylidene]methyl}-4‘,5‘-dihydro-1‘,3‘-oxazole-3β-oleate (Alsevirone-NF).

Materials and Methods: PC-3, DU-145, LnCap and 22rv1 prostate cancer cell lines were used for MTT assay. 22rv1 subcutaneous cancer xenografts in Balb/c nude mice were used for in vivo efficacy experiments. Testosterone level was determined after repeated administration of Abiraterone 20, 100 or 200 mg/kg vs Alsevirone-NF 5, 25 or 50 mg/kg daily for 14 days.

Results: Alsevirone-NF induced more significant cytotoxicity against PC3, 22rv1 and DU-145 cell lines compared to Abiraterone or Alsevirone-treated control: IC50 7.1 vs 20.6 vs 29.1 μg/ml, 7.7 vs 20.0 vs 12.7 μg/ml, 3.8 vs 43.4 vs 8.5 μg/ml, respectively. IC50 in LnCap cells was almost equal for all three studied agents, 29.2 vs 26.2 vs 30.2 μg/ml for Abiraterone, Alsevirone and Alsevirone-NF. In gonadectomized mice, significant reduction of testosterone level was observed in mice receiving Alsevirone-NF in a maximum single dose of 50 mg/kg (cumulative dose 700 mg/kg): 0.2 nmol/l vs 0.57 nmol/l in control group and 0.83 nmol/l in Abiraterone group, single dose 100 mg/kg. Statistically significant anticancer effect in vivo was obtained on day 11 after the start of treatment: Abiraterone T/C = 27% (p<0.05), Alsevirone-NF single dose 1200 mg/kg Т/С = 45% (p<0.05).

Conclusion: Alsevirone-NF exhibited higher cytotoxic activity, comparable anticancer effect in 22rv1-bearing Balb/c nude mice and provided a more significant reduction of testosterone level in gonadectomized mice in direct comparison against Abiraterone.

Keywords: Prostate cancer, alsevirone, castrate-resistant prostate cancer, 22rv1 xenografts, CYP17A1 inhibitor, cytotoxicity.

Graphical Abstract