RESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Norpregnadienos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Norpregnadienos/administração & dosagem , Células PC-3 , Ratos , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Testosterona/sangue , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Polyamine (PA) catabolism is often reduced in cancer cells. The activation of this metabolic pathway produces cytotoxic substances that might cause apoptosis in cancer cells. Chemical compounds able to restore the level of PA catabolism in tumors could become potential antineoplastic agents. The search for activators of PA catabolism among bicyclononan-9-ones is a promising strategy for drug development. The aim of the study was to evaluate the biological activity of new 3,7-diazabicyclo[3.3.1]nonan-9-one derivatives that have antiproliferative properties by accelerating PA catabolism. Eight bispidine derivatives were synthetized and demonstrated the ability to activate PA catabolism in regenerating rat liver homogenates. However, only three of them demonstrated a potent ability to decrease the viability of cancer cells in the MTT assay. Compounds 4c and 4e could induce apoptosis more effectively in cancer HepG2 cells rather than in normal WI-38 fibroblasts. The lead compound 4e could significantly enhance cancer cell death, but not the death of normal cells if PAs were added to the cell culture media. Thus, the bispidine derivative 4e 3-(3-methoxypropyl)-7-[3-(1H-piperazin-1-yl)ethyl]-3,7-diazabicyclo[3.3.1]nonane could become a potential anticancer drug substance whose mechanism relies on the induction of PA catabolism in cancer cells.
Assuntos
Antineoplásicos , Neoplasias , Animais , Antineoplásicos/química , Apoptose , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias/tratamento farmacológico , Poliaminas/química , Ratos , Relação Estrutura-AtividadeRESUMO
The polyamine (PA) metabolism is involved in cell proliferation and differentiation. Increased cellular PA levels are observed in different types of cancers. Products of PA oxidation induce apoptosis in cancer cells. These observations open a perspective to exploit the enzymes of PA catabolism as a target for anticancer drug design. The substances capable to enhance PA oxidation may become potential anticancer agents. The goal of our study was to explore how the mode of ligand binding with a PA catabolic enzyme is associated with its stimulatory or inhibitory effect upon PA oxidation. Murine N1-acetylpolyamine oxidase (5LFO) crystalline structure was used for molecular docking with ligands of various chemical structures. In vitro experiments were carried out to evaluate the action of the tested compounds upon PA oxidative deamination in a cell-free test system from rat liver. Two amino acid residues (Aps211 and Tyr204) in the structure of 5LFO were found to be significant for binding with the tested compounds. 19 out of 51 screened compounds were activators and 17 were inhibitors of oxidative deamination of PA. Taken together, these results enabled to construct a recognition model with characteristic descriptors depicting activators and inhibitors. The general tendency indicated that a strong interaction with Asp211 or Tyr204 was rather typical for activators. The understanding of how the structure determines the binding mode of compounds with PA catabolic enzyme may help in explanation of their structure-activity relationship and thus promote structure-based drug design.
Assuntos
Poliaminas/química , Poliaminas/metabolismo , Compostos de Anilina/química , Compostos de Anilina/metabolismo , Animais , Apoptose , Fluorenos/química , Fluorenos/metabolismo , Ligantes , Fígado/enzimologia , Simulação de Acoplamento Molecular , Oxirredução , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/química , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Piridinas/química , Piridinas/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A quantum field model that incorporates Bose-condensed systems near their phase transition into a superfluid phase and velocity fluctuations is proposed. The stochastic Navier-Stokes equation is used for a generation of the velocity fluctuations. As such this model generalizes model F of critical dynamics. The field-theoretic action is derived using the Martin-Siggia-Rose formalism and path integral approach. The regime of equilibrium fluctuations is analyzed within the perturbative renormalization group method. The double (ε,δ)-expansion scheme is employed, where ε is a deviation from space dimension 4 and δ describes scaling of velocity fluctuations. The renormalization procedure is performed to the leading order. The main corollary gained from the analysis of the thermal equilibrium regime suggests that one-loop calculations of the presented models are not sufficient to make a definite conclusion about the stability of fixed points. We also show that critical exponents are drastically changed as a result of the turbulent background and critical fluctuations are in fact destroyed by the developed turbulence fluctuations. The scaling exponent of effective viscosity is calculated and agrees with expected value 4/3.