Antiproliferative, proapoptotic, and tumor-suppressing effects of the novel anticancer agent alsevirone in prostate cancer cells and xenografts
| Autor: | Alexander Yu. Misharin, Vladimir A. Zolottsev, Alexandra S. Latysheva, T. S. Spirina, Marina N Yakunina, Marina V Komarova, Natalia Y Anisimova, Vadim S. Pokrovsky, Tatiana A Nitetskaya, Darina V. Sokolova, Irina I Khan, Saida S Karshieva |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Norpregnadienes Pharmaceutical Science Mice Nude Caspase 3 Antineoplastic Agents Apoptosis Pharmacology Inhibitory Concentration 50 Mice In vivo Cell Line Tumor Drug Discovery LNCaP Cytotoxic T cell Animals Humans Testosterone Cell Proliferation Mice Inbred BALB C Chemistry Prostatic Neoplasms Steroid 17-alpha-Hydroxylase Xenograft Model Antitumor Assays In vitro Rats PC-3 Cells Microsome |
| Zdroj: | Archiv der PharmazieREFERENCES. 355(1) |
| ISSN: | 1521-4184 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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