RESUMO
Mifepristone (RU486) is a chemical contraceptive marketed in more than 55 countries and used by hundreds of millions of women worldwide. Current studies reported its uses by both genders for a safe and long-term psychotic depression and particularly for traditional cancer chemotherapy. Here, we investigated the multidisciplinary data from recent large epidemiological chemoprevention studies for long-term use of oral contraceptives to reduce cancer risk, and from the unsuccessful clinical trials of mifepristone used as a post-metastatic anticancer drug, and elucidated the similarities and differences in cellular and molecular processes between embryonic implantation to endometrium and adhesion/invasion of circulating tumor cells (CTCs) to vascular endothelium. The deep analyses provide a stronger scientific basis for repurposing abortifacients for safe and effective cancer metastatic chemoprevention. Initiation of such cancer drug development strategy represents a paradigm shift from traditional post-metastasis treatments to novel pre-metastasis chemoprevention.
Assuntos
Abortivos , Antineoplásicos , Abortivos/química , Abortivos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Quimioprevenção , Feminino , Humanos , Masculino , Mifepristona/química , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/prevenção & controleRESUMO
Recent global epidemiological studies revealed the lower ovarian cancer death from long-term use of oral contraceptives. However, the underlying mechanism of action is not clear. Here, we use the abortifacient metapristone (RU486 derivative) to test the hypothesis that the contraceptives might interrupt CXCL12/CXCR4 chemokine axis to inhibit ovarian cancer metastasis. Metapristone at concentrations (Assuntos
Antineoplásicos/uso terapêutico
, Quimiocina CXCL12/metabolismo
, Mifepristona/análogos & derivados
, Invasividade Neoplásica/prevenção & controle
, Neoplasias Epiteliais e Glandulares/patologia
, Neoplasias Ovarianas/patologia
, Neoplasias Peritoneais/prevenção & controle
, Neoplasias Peritoneais/secundário
, Receptores CXCR4/metabolismo
, Abortivos/química
, Abortivos/farmacologia
, Abortivos/uso terapêutico
, Animais
, Antineoplásicos/química
, Antineoplásicos/farmacologia
, Carcinoma Epitelial do Ovário
, Adesão Celular/efeitos dos fármacos
, Linhagem Celular Tumoral
, Movimento Celular/efeitos dos fármacos
, Proliferação de Células/efeitos dos fármacos
, Quimioprevenção
, Feminino
, Humanos
, Camundongos Endogâmicos BALB C
, Camundongos Nus
, Mifepristona/química
, Mifepristona/farmacologia
, Mifepristona/uso terapêutico
, Invasividade Neoplásica/patologia
, Neoplasias Epiteliais e Glandulares/tratamento farmacológico
, Neoplasias Epiteliais e Glandulares/metabolismo
, Neoplasias Ovarianas/tratamento farmacológico
, Neoplasias Ovarianas/metabolismo
, Ovário/efeitos dos fármacos
, Ovário/metabolismo
, Ovário/patologia
, Neoplasias Peritoneais/metabolismo
, Neoplasias Peritoneais/patologia
, Peritônio/efeitos dos fármacos
, Peritônio/metabolismo
, Peritônio/patologia
, Transdução de Sinais/efeitos dos fármacos
RESUMO
Recent large epidemiological studies demonstrated benefit of oral contraceptives in reducing cancer risk, and our analysis also showed molecular and cellular similarities between embryo implantation and CTCs adhesion-invasion to endothelium. We here hypothesize that abortion traditional Chinese medicine (TCM) may serve well for pre-metastatic chemoprevention. To test the hypothesis, we selected the safe and well-known abortifacient TCM Murraya paniculata and identified a most-promising extracted fraction G (containing flavonoids and coumarins) from its many raw ethanol/dichloromethane extracts by using the bioactivity-guided fast screen assay. G showed free radical scavenging effect, and specifically inhibited both embryo implantation to human endometrial bed and cancer HT29 cells to human endothelium in a concentration-dependent manner (1-30 µg/mL) without significant cytotoxicity demonstrated by its high adhesion inhibition ratio. The inhibition may result from its down-regulation on expression of integrin ß1 and α6, and CD44 on HT29 cells, as well as E-selectin on endothelial cells. Furthermore, G inhibited invasion and migration of HT29 cells. Pretreatment followed by one-month oral administration of G to the immunocompetent mice inoculated with mouse melanoma cells produced significant inhibition on lung metastasis without marked side effects. Collectively, this paradigm-shifting study provides, for the first time, a new strategy to discover safe and effective pre-metastatic chemopreventives from abortion TCM.
Assuntos
Abortivos/química , Quimioprevenção/métodos , Medicina Tradicional Chinesa/métodos , Murraya/química , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Células HT29 , Humanos , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Medicina Tradicional Chinesa/tendências , Melanoma Experimental/patologia , Melanoma Experimental/prevenção & controle , Camundongos Endogâmicos C57BL , Extratos Vegetais/análise , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologiaRESUMO
OBJECTIVE: Observing the effect of phenolic acids from Arnebia euchroma assist mifepristone in anti-early pregnancy of SD rattus norvegicus. METHOD: Feed the SD rattus norvegicus with phenolic acids from A. euchroma during the 7 th to 9 th day, and then we observe the restaining rate of pregnancy. At the same time, we determine the progesterone level in blood serum in the ways of radioimmunoassay. RESULT: 720 g x kg(-1) enolic aids from A. euchroma can markedly increase the restaining rate of pregnancy (P < 0.05) than that only mifepristone dose (8.0 g x kg(-1)). In addition, the number of everage still bith increase, however, to the pogesterone level in blood serum. It has little effect. CONCLUSION: The effect of phenolic acids from A. euchroma assist mifepristone in anti-early pregnancy of SD rattus norvegicus is clear, and it dosen't work in the ways of decreasing the pogesterone level.