The Inhibition Effects And Mechanism Of IGF-1R Inhibitor Picropodophyllin In Colon Cancer

Objective:In this study,firstly we built a nude mice xenograft model and injected PPP intraperitoneal.Then we observed the growth of xenograft and analyzed the expression of IGF-1R as well as its downstream AKT,ERK to investigate the inhibition effects and mechanism of IGF-1R inhibitor Picropodophyllin in colon carcinoma.Furthermore,we want to find probable side effects so that we can evaluate the safety and clinical value of PPP in the future.Methods:Firstly we prepared for the HT-29 suspension and injected into the right axilla of balb/c nude mice to built colon cancer xenograft model.When the volume of tumor reached the standard level,ten 4-6 weeks balb/c nu/nu mice were randomly devided into two groups:treatment group and control group,each group had 5 mice.the treatment group gave an intraperitoneal injection of PPP twice a day while the control group injected saline instead.We measured the volume of tumor every two days.Ten days later,all mice were sacrificed after blood samples collection.The transplanted tumor was separated and weighed.The next step was comparing blood glucose,ALT,AST,ALB,BUN and SCr between two groups to estimate if the drug has side effects on the glucose metabolize as well as liver and kidney function.Furthermore,We collected all data about the volume of tumor and drew a growth curve to illustrated the growth trend after given the therapy.Western-blot was utilized after protein extraction to examine the expression of IGF-1R,AKT and ERK between two groups and we applied independent sample t test to analyze if the results have statistical significance.Results:1.The transplanted tumor volume and weight of two groups:From the external dimension we can easily find that tumor volume in treatment group were smaller than control group.After calculated all the data of volume and weight by statistic software The conclusion was the same as we observed before and differences between the groups were statistically significant(P=0.008,0.038,P<0.05).2.The comparison of blood sample between two groups:The Blood glucose,AST,ALB,BUN and SCr in treatment group have no statistic significance when compared with control group(all P value>0.05).However,we paid attention to index of ALT which was higher in treatment group(P=0.006,P<0.05).3.The expression level of IGF-1R and downstream AKT,ERK:The expression level of all factors in treatment group was lower than control group after therapy.The difference has statistic meaning(P=0.049,0.039,0.010,P<0.05).Conclusions:1.The picropodophyllin can effectively inhibit the growth of colon cancer from the observation of tumor external appearance.2.The mechanism of Picropodophyllin in colon cancer may be the inhibition of IGF-1R as well as downregulation of downstream signal pathway PI3K/AKT and MAPK/ERK thus suppresses the proliferation and induces tumor apoptosis.3.No mice in treatment group were found adverse reaction during the drug therapy.The drug showed little influence in blood glucose and kidney function.Moreover,this drug excert little effect on AST and ALB which is also used to evaluate the liver function.This,to some extent,provides a potent evidence that the drug is little toxicity and high security.For ALT,it is not sure if the rise of ALT has relationship with toxicity of the drug on liver and we should enlarge the sample to take a further exploration.4.In conclusion,the small molecule IGF-1R inhibitor Picropodophy-1 lin may provide a new way on target therapy of colon cancer.