Antiproliferative, proapoptotic, and tumor‐suppressing effects of the novel anticancer agent alsevirone in prostate cancer cells and xenografts
- 19 October 2021
- journal article
- research article
- Published by Wiley in Archiv der Pharmazie
- Vol. 355 (1), e2100316
- https://doi.org/10.1002/ardp.202100316
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. IC50 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 IC50 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.Keywords
Funding Information
- Russian Foundation for Basic Research (20‐315‐90043)
This publication has 31 references indexed in Scilit:
- Synthesis of 21-nitrogen substituted pregna-5,17(20)-dienes from pregnenoloneSteroids, 2012
- Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): Head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft modelSteroids, 2011
- CYP17 inhibitors for prostate cancer therapyThe Journal of Steroid Biochemistry and Molecular Biology, 2011
- Abiraterone and Increased Survival in Metastatic Prostate CancerThe New England Journal of Medicine, 2011
- 17α-Hydroxylase/17,20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress responseMolecular Cancer Therapeutics, 2008
- Inhibition of 17α-Hydroxylase/C17,20-Lyase (CYP17) from Rat Testis by Green Tea Catechins and Black Tea TheaflavinsBioscience, Biotechnology, and Biochemistry, 2007
- Expression and Nuclear Localization of ErbB3 in Prostate CancerClinical Cancer Research, 2006
- The phosphorylation status and anti‐apoptotic activity of Bcl‐2 are regulated by ERK and protein phosphatase 2A on the mitochondriaFEBS Letters, 2004
- Pyridyl Substituted Benzocycloalkenes: New Inhibitors of 17α-Hydroxylase/ 17,20-Lyase (P450 17α)Journal of Enzyme Inhibition, 1994
- Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assaysJournal of Immunological Methods, 1983