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Alsevirone-NF Reduces Serum Testosterone and Inhibits Prostate Cancer Xenograft Growth in Balb/c Nude Mice

[ Vol. 7 , Issue. 2 ]

Author(s):

Vadim S. Pokrovsky*, Vladimir A. Zolottsev, Alexandra S. Latysheva, Vasiliy A. Kudinov, Natalia Yu Anisimova, R.L.M. Almanza, Olga Yu Alekseeva, Konstantin K. Baskaev, Galina B. Smirnova, Yulia A. Borisova and Olga M. Ipatova   Pages 113 - 118 ( 6 )

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.

Affiliation:

N.N. Blokhin Cancer Research Center, Moscow, Institute of Biomedical Chemistry, Moscow, Institute of Biomedical Chemistry, Moscow, Institute of General Pathology and Pathophysiology, Moscow, N.N. Blokhin Cancer Research Center, Moscow, Peoples' Friendship University, Moscow, Peoples' Friendship University, Moscow, Institute of General Pathology and Pathophysiology, Moscow, N.N. Blokhin Cancer Research Center, Moscow, N.N. Blokhin Cancer Research Center, Moscow, Institute of Biomedical Chemistry, Moscow

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