Antiproliferative activity of the novel CYP17A1 inhibitor alsevirone

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Abstract

BACKGROUND: Prostate cancer is the most frequently diagnosed type of cancer in men in developed countries. It is dependent upon androgens and could be effectively combated by androgen deprivation therapy. Reduction of androgen synthesis can be accomplished through the inhibition of the enzyme 17α-hydroxylase/17.20-lyase (CYP17A1), which catalyzes two sequential reactions in the production of androgens. Steroid derivatives modified with nitrogen-containing heterocycles attract attention as antineoplastic agents for prostate cancer treatment due to their inhibitory potential against CYP17A1.

AIM: Evaluate cytotoxic activity and antitumor effects of the synthesized alsevirone in comparison with abiraterone.

METHODS: Cytotoxicity was evaluated using MTT test. Anticancer effect was researched in vivo in prostate cancer xenograft models 22Rv1 and DU145 in Balb/c nude mice. Testosterone concentration was determined using an enzyme-linked immunosorbent assay in blood serum of BDF1 mice.

RESULTS: Alsevirone demonstrated cytotoxic activity in prostate cancer cells: DU145 (23.8±1.2 µM vs 151.4±23.7 µM for abiraterone), 22Rv1 (35.9±5.6 µM vs 109.9±35.2 µM for abiraterone) and LNCaP (22.9±0.5 µM vs 28.8±1.6 µM for abiraterone). Testosterone concentration in blood serum of BDF1 mice reduced by 80% after 10-day treatment. Inhibition of the tumors’ growth in 22Rv1 xenograft model was statistically significant when using alsevirone in comparison with the control group: average tumor volume was 171.6±50.1 mm3 (р=0.022) vs 424.2±70.3 mm3 in control, with tumor growth inhibition index of 59%.

CONCLUSIONS: Alsevirone has a higher cytotoxic potential against prostate cancer cells (DU145, LNCaP and 22Rv1) compared to abiraterone. Alsevirone demonstrated the ability to reduce the concentration of testosterone in the blood serum of BDF1 mice, and statistically significant antitumor activity in 22Rv1 xenograft models.

About the authors

Irina I. Khan

N.N. Blokhin National Medical Research Center of Oncology; Peoples’ Friendship University of Russia

Email: irinchek05@gmail.com
ORCID iD: 0000-0003-2948-0872
SPIN-code: 6826-7694

Cand.  Sci. (Bio.)

Russian Federation, 24 Kashirskoe shosse, Moscow 115478; Moscow

Alexandra S. Latysheva

Institute of Biomedical Chemistry

Email: aidanlinch@gmail.com
ORCID iD: 0000-0001-6669-5739
SPIN-code: 6572-2192
Russian Federation, Moscow

Vladimir A. Zolottsev

Peoples’ Friendship University of Russia; Institute of Biomedical Chemistry

Email: vazolottsev@mail.ru
ORCID iD: 0000-0002-2067-5887
SPIN-code: 7787-5961

Cand.  Sci. (Chem.)

Russian Federation, Moscow; Moscow

Elena A. Demidova

N.N. Blokhin National Medical Research Center of Oncology

Email: badjito@mail.ru
ORCID iD: 0000-0002-6511-3423
Russian Federation, 24 Kashirskoe shosse, Moscow 115478

Tatyana S. Spirina

N.N. Blokhin National Medical Research Center of Oncology

Email: spirtatjana@yandex.ru
ORCID iD: 0000-0001-7631-3116
Russian Federation, 24 Kashirskoe shosse, Moscow 115478

Saida S. Karshieva

N.N. Blokhin National Medical Research Center of Oncology

Email: skarshieva@gmail.com
ORCID iD: 0000-0003-2469-2315
SPIN-code: 9154-7071

Cand.  Sci. (Bio.)

Russian Federation, 24 Kashirskoe shosse, Moscow 115478

Darina V. Sokolova

N.N. Blokhin National Medical Research Center of Oncology; Peoples’ Friendship University of Russia

Email: d.v.sokolova@gmail.com
ORCID iD: 0000-0003-3972-2425
SPIN-code: 2960-4800

Cand.  Sci. (Bio.)

Russian Federation, 24 Kashirskoe shosse, Moscow 115478; Moscow

Marina N. Yakunina

N.N. Blokhin National Medical Research Center of Oncology

Email: irsovet@yandex.ru
ORCID iD: 0000-0002-5278-1641

Dr. Sci. (Vet.)

Russian Federation, 24 Kashirskoe shosse, Moscow 115478

Marina V. Komarova

Peoples’ Friendship University of Russia; Samara National Research University

Email: marinakom@yandex.ru
ORCID iD: 0000-0002-0065-4990
SPIN-code: 4359-2715

Cand. Sci. (Bio.)

Russian Federation, Moscow; Samara

Alexander Yu. Misharin

Institute of Biomedical Chemistry

Email: amisharin48@gmail.com
ORCID iD: 0000-0002-5328-716X

Dr. Sci. (Bio.)

Russian Federation, Moscow

Vadim S. Pokrovsky

N.N. Blokhin National Medical Research Center of Oncology; Peoples’ Friendship University of Russia

Author for correspondence.
Email: v.pokrovsky@ronc.ru
ORCID iD: 0000-0003-4006-9320
SPIN-code: 4552-1226

MD, Dr. Sci. (Med.), Assistant Professor

Russian Federation, 24 Kashirskoe shosse, Moscow 115478; Moscow

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Supplementary files

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2. Fig. 1. Structures of the title compounds: a — alsevirone, 2’-[((E)-3β-hydroxyandrost-5-en-17-ylidene)methyl]-4’,5’-dihydro-1’,3’-oxazole; b — abiraterone, 3-(3β-hydroxyandrosta-5,16-dien-17-yl)-pyridine.

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3. Fig. 2. Effects of alsevirone and abiraterone on testosterone production in BDF1 mice. Alsevirone and abiraterone were administered in a single dose of 300 mg/kg for 10 days. Data are expressed as mean ± standard error. * — р ≤0,05 was considered as significant.

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4. Fig. 3. Effects of alsevirone and abiraterone on the viability of prostate cancer cell lines. LNCaP, DU145, 22Rv1, and PC3 cells were treated with 0.4–100 mg/ml alsevirone and abiraterone for 72 h. Error bars indicate mean ± standard deviation at n=3. All values are significant at р ≤0.05.

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5. Fig. 4. Dynamics of tumor growth on the DU145 xenograft model after 10-day treatment with alsevirone and abiraterone at doses of 150 mg/kg and 300 mg/kg, compared with the control group.

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6. Fig. 5. Dynamics of tumor growth on the 22Rv1 xenograft model after 10-day treatment with alsevirone and abiraterone at doses of 150 mg/kg and 300 mg/kg, compared with the control group.

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