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

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, Olga M. Ipatova

Journal Name: Clinical Cancer Drugs

Volume 7 , Issue 2 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


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.

[1]
Scher HI, Morris MJ, Stadler WM, et al. Prostate Cancer Clinical Trials Working Group 3. Trial design and objectives for castration-resistant prostate cancer: Updated recommendations from the prostate cancer clinical trials working group 3. J Clin Oncol 2016; 34(12): 1402-18.
[http://dx.doi.org/10.1200/JCO.2015.64.2702] [PMID: 26903579]
[2]
Bruno RD, Vasaitis TS, Gediya LK, et al. 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 model. Steroids 2011; 76(12): 1268-79.
[http://dx.doi.org/10.1016/j.steroids.2011.06.002] [PMID: 21729712]
[3]
Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 2008; 26(28): 4563-71.
[http://dx.doi.org/10.1200/JCO.2007.15.9749] [PMID: 18645193]
[4]
Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol 2010; 28(9): 1496-501.
[http://dx.doi.org/10.1200/JCO.2009.25.9259] [PMID: 20159814]
[5]
Toren PJ, Kim S, Pham S, et al. Anticancer activity of a novel selective CYP17A1 inhibitor in preclinical models of castrate-resistant prostate cancer. Mol Cancer Ther 2015; 14(1): 59-69.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0521] [PMID: 25351916]
[6]
Montgomery R, Eisenberger M, Rettig M, et al. Phase I clinical trial of galeterone (TK-001), a multifunctional antiandrogen and CYP17 inhibitor in castration resistant prostate cancer (CRPC). J Clin Oncol 2012; 30: 4665.
[http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4665]
[7]
Kostin VA, Zolottsev VA, Kuzikov AV, et al. Oxazolinyl derivatives of [17(20)E]-21-norpregnene differing in the structure of A and B rings. Facile synthesis and inhibition of CYP17A1 catalytic activity. Steroids 2016; 115: 114-22.
[http://dx.doi.org/10.1016/j.steroids.2016.06.002] [PMID: 27505042]
[8]
Zolottsev VA, Tkachev YV, Latysheva AS, et al. Comparison of [17(20)E]-21-Norpregnene oxazolinyl and benzoxazolyl derivatives as inhibitors of CYP17A1 activity and prostate carcinoma cells growth. Steroids 2018; 129: 24-34.
[http://dx.doi.org/10.1016/j.steroids.2017.11.009] [PMID: 29183745]
[9]
Latysheva AS, Zolottsev VA, Veselovsky AV, et al. New steroidal oxazolines, benzoxazoles and benzimidazoles related to abiraterone and galeterone. Steroids 2020; 153: 108534
[http://dx.doi.org/10.1016/j.steroids.2019.108534] [PMID: 31678134]
[10]
Immordino ML, Dosio F, Cattel L. Stealth liposomes: Review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomedicine 2006; 1(3): 297-315.
[PMID: 17717971]
[11]
Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 2005; 4(2): 145-60.
[http://dx.doi.org/10.1038/nrd1632] [PMID: 15688077]
[12]
Matteucci ME, Brettmann BK, Rogers TL, Elder EJ, Williams RO III, Johnston KP. Design of potent amorphous drug nanoparticles for rapid generation of highly supersaturated media. Mol Pharm 2007; 4(5): 782-93.
[http://dx.doi.org/10.1021/mp0700211] [PMID: 17715989]
[13]
Solymosi T, Ötvös Z, Angi R, et al. Novel formulation of abiraterone acetate might allow significant dose reduction and eliminates substantial positive food effect. Cancer Chemother Pharmacol 2017; 80(4): 723-8.
[http://dx.doi.org/10.1007/s00280-017-3406-6] [PMID: 28776077]
[14]
Solymosi T, Ötvös Z, Angi R, et al. Development of an abiraterone acetate formulation with improved oral bioavailability guided by absorption modeling based on in vitro dissolution and permeability measurements. Int J Pharm 2017; 532(1): 427-34.
[http://dx.doi.org/10.1016/j.ijpharm.2017.09.031] [PMID: 28919099]
[15]
Goldwater R, Hussaini A, Bosch B, Nemeth P. Comparison of a novel formulation of abiraterone acetate vs. the originator formulation in healthy male subjects: Two randomized, open-label, crossover studies. Clin Pharmacokinet 2017; 56(7): 803-13.
[http://dx.doi.org/10.1007/s40262-017-0536-2] [PMID: 28425029]
[16]
Ylitalo EB, Thysell E, Thellenberg-Karlsson C, et al. Marked response to cabazitaxel in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of acquired resistance by anti-androgens. Prostate 2020; 80(2): 214-24.
[http://dx.doi.org/10.1002/pros.23935] [PMID: 31799745]
[17]
Vázquez R, Civenni G, Kokanovic A, et al. Efficacy of novel bromodomain and extraterminal inhibitors in combination with chemotherapy for castration-resistant prostate cancer Eur Urol Oncol 2019; S2588-9311(19)30116-6.
[http://dx.doi.org/10.1016/j.euo.2019.07.013]
[18]
Fahrenholtz CD, Rick FG, Garcia MI, et al. Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer. Proc Natl Acad Sci USA 2014; 111(3): 1084-9.
[http://dx.doi.org/10.1073/pnas.1323102111] [PMID: 24395797]
[19]
Dyshlovoy SA, Otte K, Alsdorf WH, et al. Marine compound rhizochalinin shows high in vitro and in vivo efficacy in castration resistant prostate cancer. Oncotarget 2016; 7(43): 69703-17.
[http://dx.doi.org/10.18632/oncotarget.11941] [PMID: 27626485]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 7
ISSUE: 2
Year: 2020
Published on: 10 May, 2020
Page: [113 - 118]
Pages: 6
DOI: 10.2174/2212697X07999200511082225
Price: $25

Article Metrics

PDF: 279
HTML: 2