Therapeutic effect of IGF-1R-targeting inhibitor (TAE226) on malignant pleural effusion in nude mice

Abstract

To study the therapeutic effect of IGF-1R inhibitor TAE226 on malignant pleural effusion (MPE) in nude mice. Human lung carcinoma A549 cells were injected into the pleural cavity of nude mice to establish MPE model. The mice were randomly divided into model group and treatment group, and were orally administered with distilled water and TAE226 (20 mg/kg) in the same volume, respectively. The volume of pleural effusion and tumor weight of the two groups were observed. HE staining was used to reveal the histological changes and enzyme-linked immunosorbent assay (ELISA) was used to detect the IGF-1R protein expression. IGF-1R mRNA level in the tumor tissue was determined by RT-PCR. Microvessel density (MVD) and cell proliferation index (PI) were assessed by immunohistochemical analysis. The protein expression levels of IGF-1R, p-IGF-1R, PI3K and p-PI3K in the tumor tissue were determined by Western blotting. The volumes of pleural effusion were (241.4±89.7) μl and (121.7±78.8) μl in the model and treatment groups, respectively (P<0.05). The tumor weight of treatment group was (316.7±186.3) mg, significantly lower than that of the model group (671.4±281.4) mg (P<0.05). RT-PCR analysis showed that IGF-1R mRNA level was 0.914±0.029 in the treatment group, significantly lower than that of the model group (1.152±0.037, P<0.01). The ELISA data revealed that IGF-1R protein expression level of the model group was significantly higher than that of the treatment group [(41.0±4.7) μg/L vs. (24.0±3.1) μg/L, P<0.01]. Immunohistochemical analysis showed that there were significant differences between MVD and PI in the model and treatment groups [MVD, 34.75±3.49 vs. 22.25±3.63; PI, (75.25±7.15)% vs. (45.75±5.12)%; P<0.01 for both). Western blot data showed that IGF-1R and PI3K protein expression levels were not significantly different between the model and treatment groups (1.03±0.33 vs. 0.98±0.37 and 1.05±0.28 vs. 0.98±0.19), respectively (P>0.05), but p-IGF-1R and p-PI3K protein expression levels had significant differences between the two groups (1.08±0.10 vs. 0.51±0.08 and 1.12±0.09 vs. 0.86±0.09), respectively (P<0.01 for both). The IGF-1R inhibitor can effectively inhibit the formation of malignant pleural effusion. Its mechanism may be related to the suppression of tumor cell proliferation, invasion and angiogenesis through inhibition of PI3K signaling. TAE226 treatment may be a potential therapeutic regimen of treating malignant pleural effusion.