RESUMO
The insulin growth factor-I receptor (IGF1R) signaling is a key mechanism for osteosarcoma (OS) cell proliferation. GSK1904529A is a novel small molecule IGF1R kinase inhibitor. Its activity against OS cells was tested. In both established OS cell lines (Saos-2 and MG-63) and primary human OS cells, treatment with GSK1904529A (at nM concentrations) significantly inhibited cell proliferation. At the molecular level, GSK1904529A almost completely blocked IGF1R activation in OS cells, and inhibited downstream AKT-ERK activation. IGF1R silence by targeted shRNA also inhibited AKT-ERK activation and Saos-2 cell proliferation. Significantly, GSK1904529A was unable to further inhibit proliferation of IGF1R-silenced Saos-2 cells. In vivo, GSK1904529A administration orally inhibited Saos-2 tumor growth in nude mice. Together, these results suggest that targeting IGF1R by GSK1904529A inhibits OS cell growth in vitro and in vivo.
Assuntos
Antineoplásicos/farmacologia , Imidazóis/farmacologia , Piridinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3 , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To study on the prevalence of body overweight and obesity in China and its distribution in age, sex and economic development status. METHODS: A total of 209,849 in all ages from the 2002 China National Nutrition and Health Survey (NNAHS) database were analyzed. The year 2000 population census data was used for age standardization. 1978 WHO criteria using Z scores was applied to age 0-7 years, criteria recommended by the Working Group on Obesity in China was applied to those aged 7-17 years and criteria in the Guidelines for Prevention and Control of Overweight and Obesity in Chinese Adults was applied to those aged 18 years and above. RESULTS: The overall prevalence was 17.6% for overweight and 5.6% for obesity. The combined prevalence of overweight and obesity was 23.2%. The prevalence of overweight was 25.0%, 21.6%, 17.4%, 15.1%, 19.2% and 12.8%, respectively for large city, middle-and-small city, class 1 rural, class 2 rural, class 3 rural and class 4 rural. For obesity, the rate was 10.6%, 7.2%, 6.4%, 4.3%, 6.0% and 2.7%, respectively for large city, middle-and-small city, class 1 rural, class 2 rural, class 3 rural and class 4 rural. By age groups, the prevalence of overweight was 3.4% in children age 0-6, 4.5% in adolescents age 7-17, 22.8% in adults age 18 and above; the prevalence of obesity was 2.0% in children age 0-6, 2.7% in adolescents age 7-17, 7.1% in adults age 18 and above. The sex difference in overweight and obesity differed between urban and rural, and among age groups. CONCLUSION: Overweight and obesity should have affected nearly 1 quarter of the country's total population, and became a threatening hazard to resident's health. As the urbanization progress, obesity might doubly increase. Prevention and control of this hazard should be urgently needed.