Antiproliferative, proapoptotic, and tumor-suppressing effects of the novel anticancer agent alsevirone in prostate cancer cells and xenografts

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. © 2021 Deutsche Pharmazeutische Gesellschaft

Khan I.I. 1, 2 , Karshieva S.S.1 , Sokolova D.V. 1, 2 , Spirina T.S.1 , Zolottsev V.A. 2, 3 , Latysheva A.S.3 , Anisimova N.Y.1, 4 , Komarova M.V. 5 , Yakunina M.N.1 , Nitetskaya T.A.1 , Misharin A.Y.3 , Pokrovsky V.S. 1, 2, 6
  • 1 Laboratory of combined treatment, N. N. Blokhin National Medical Research Center of Oncology of Ministry of Health of Russian Federation, Moscow, Russian Federation
  • 2 Department of biochemistry, RUDN University, Moscow, Russian Federation
  • 3 Laboratory of synthesis of physiologically active compounds, Institute of Biomedical Chemistry, Moscow, Russian Federation
  • 4 Laboratory of polymer materials, NUST “MISIS”, Moscow, Russian Federation
  • 5 Department of laser and biotechnical systems, Samara University, Samara, Russian Federation
  • 6 Center of genetics and life sciences, Sirius University of Science and Technology, Sochi, Krasnodarsky Kray, Russian Federation
Ключевые слова
anticancer activity; antiproliferative agents; antitumor activity; cancer treatment; inhibitors
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Orazov M.R., Radzinsky V.E., Orekhov R.E.
Гинекология. Общество с ограниченной ответственностью Медицинское маркетинговое агентство МедиаМедика. Том 23. 2021. С. 314-323