RESUMO
PURPOSES: To evaluate the antiproliferative activity of contragestazol (DL111-IT) in vitro and in vivo and to elucidate potential molecular mechanisms. METHODS: Cell killing ability of DL111-IT was measured by MTT/Trypan blue exclusion method and murine and human tumor models; cell cycle was analyzed by flow cytometry; pRb, CDK4 and Cyclin D1 expressions were detected by western blotting. RESULTS: DL111-IT exhibited high efficiency on cell growth inhibition of 12 cancer cell lines, the IC50 values were 4.1-19.7 microg/ml. In Sarcoma-180 (S180) and Hepatoma-22 (H22) tumor bearing mice models, the inhibition rates were 55.9 and 55.6%, respectively, at the doses of DL111-IT 12.5-50.0 mg/kg for 9 days consecutive administration. Human ovarian carcinoma (HO-8910) xenograft study showed that, nine administrations (within 15 days) of DL111-IT (12.5-50.0 mg/kg) significantly inhibited tumor growth with the inhibition rates ranging from 17.0 to 64.3%. DL111-IT induced G1 arrest and overexpression of pRb, CDK4 and Cyclin D1 were observed in HO-8910 cell line, suggesting that cell cycle regulation might contribute to the anticancer property of DL111-IT. CONCLUSIONS: DL111-IT could inhibit the proliferation of cancer cells both in vitro and in vivo via a cell cycle regulation pathway.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Triazóis/farmacologia , Animais , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
AIM: To evaluate the antiproliferative activity of contragestazol (DL111-IT) on the human prostate cancer cell line PC3 in vitro and in vivo and to elucidate its potential molecular mechanisms. METHODS: The cell killing ability of DL111-IT was measured by the 3-(4,5-dimethylthia-zol,2-yl)-2,5-diphenyltetrazolium bromide (MTT) reagent assay method and the tumor xenograft model. The cell cycle was analyzed by flow cytometry and protein expression, including retinoblastoma (pRb), cyclin-dependent kinase 4 (CDK4) and cyclin D1, was detected by Western blotting. RESULTS: DL111-IT exhibited high efficiency on cell growth inhibition of the human androgen-independent prostate cancer cell line PC3. The drug concentration that yielded 50% cell inhibition (IC50 value) was 9.9 mg/mL. In the PC3 tumor xenograft study, DL111-IT (1.25 mg/kg-20.0 mg/kg) given once a day for 10 days significantly inhibited tumor growth, with the inhibition rate ranging from 21% to 50%. Flow cytometric analysis indicated that DL111-IT could cause G1 arrest in the PC3 cell line, but not apoptosis. DL111-IT enhanced pRb expression and down-regulated CDK4 and cyclin D1 expression, suggesting that cell cycle regulation might contribute to the anticancer property of DL111-IT. CONCLUSION: DL111-IT inhibits the proliferation of human androgen-independent prostate cancer cell line PC3 in vitro and in vivo by a cell cycle regulation pathway.
Assuntos
Androgênios/farmacologia , Imunossupressores/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Triazóis/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Feminino , Fase G1/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Neoplasias da Próstata/patologia , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Proteína do Retinoblastoma/metabolismo , Transplante HeterólogoRESUMO
This study evaluated the effectiveness and acute toxicity of DL111-IT combined with mifepristone (RU486) and misoprostol (MISO) on early pregnancy termination. In the pregnant rats experiments, the ED(50) values of RU486 in two-drug combinations were 0.16 (combined with DL111-IT) and 0.40 (combined with MISO) mg x kg(-1) x d(-1), while in three-drug combination treatment group (DL111-IT 9.0 mg x kg(-1) (Assuntos
Abortivos não Esteroides/toxicidade
, Abortivos Esteroides/administração & dosagem
, Aborto Induzido
, Mifepristona/administração & dosagem
, Misoprostol/administração & dosagem
, Triazóis/toxicidade
, Animais
, Columbidae
, Sinergismo Farmacológico
, Quimioterapia Combinada
, Feminino
, Cobaias
, Masculino
, Camundongos
, Gravidez
, Primeiro Trimestre da Gravidez
, Ratos
, Ratos Sprague-Dawley
, Útero/efeitos dos fármacos
, Vômito/induzido quimicamente