Study Of The Activities And Mechanisms Of Prieventing And Treatng Colorectal Cancer Of Caffeic Acid 3,4-dihydroxyphenethyl Ester

Objectives:Colorectal cancer(CRC)is the third diagnosed cancer and the fourth death cause of cancer in the world,and its incidence and mortality is increasing.However,existing drugs fail in CRC prevention and treatment.Previous study indicated that small-molecule caffeic acid 3,4-dihydroxyphenethyl ester(CADPE)from Sarcandra glabra has the potential to prevent and treat CRC.Therefore,we undertake a study on the efficacy of CADPE preventing and treating CRC,and explore the related molecular mechanism.Methods:Chronic enteritis plays a crucial role in the occurrence and development of CRC,so we uses the enteritis-associated colorectal cancer model in mice by 1,2-dimethylhydrazine(DMH)combined dextran sulfate sodium(DSS)to study the efficacy of CADPE preventing and treating CRC,and explore the related molecular mechanism.We use CADPE intervention in the whole stage?early stage and later stage of the CRC development respectively,observing the incidence of CRC,tumor number,tumor size,and observing the proliferation and apoptosis of tumor cells,key pro-tumor transcription factors STAT,NF-?B,C-Myc,?-Catenin level,angiogenesis,inflammatory cells infiltration to explore the molecular mechanism.Study compares related indicators to facilitate getting CADPE preventing CRC characteristics compared with known drugs sodium butyrate(SB)and Aspirin.Subsequently,use CADPE to treat animals with CRC,and observe the proliferation and apoptosis of cancer cells,key promoting cnacer transcription factors level and inflammatory cell infiltration to study therapeutic effects and potential molecular mechanism.Results: CADPE can prevent CRC,the whole or early stage intervention is effective,but the later stage intervention is ineffective.The whole stage intervention: compared with model group,CADPE significantly decrease CRC incidence,tumor volume,tumor number without 4 mm diameter tumor;Sodium butyrate only reduced tumor volume.Early stage intervention: compared with model group,CADPE significantly reduce the tumor volume and tumor number,the tumor with the diameter more than 4 mm is reduced near 1/3.However,aspirin did not see any preventive effect of CRC in the early stage intervention.Later stage intervention: CADPE did not have obvious effect.However,aspirin can significantly reduce tumor incidence and tumor number.Therefore,in order to understand the reason of CADPE preventing CRC in the early stage and forming process,the molecular mechanism of CADPE preventing CRC was further explored.Study demostrates: 1)During the acute inflammatory injury Period of intestinal tissue,CADPE can inhibit the expression of ?-Catenin in crypt foci,decrease the expression of NF-?B in monocytes and reduce intestinal epithelial cell damage.2)During repair period after acute damage,CADPE inhibits the expression of ?-Catenin in the crypt foci and induces the recruitment of monocytes at the epithelial layer,which may be beneficial to the removal of damaged or diseased intestinal epithelial cells.3)During CRC forming process,CADPE reduces tumor cells by decreasing the key tumor promoting transcription factor(c-Myc,PCNA,Cyclin D1),angiogenesis factor(VEGF),promoting anti-apoptosis protein(Survivin)and reducing the infiltration of T cells and monocytes.Effect of CADPE treating CRC: CRC animals are treated with more than CRC prevention dose CADPE for 5 weeks,and study shows that high dose CADPE can significantly inhibit tumor promoting key transcription factors(c-Myc,NF-?B,p-Stat3 and ?-Catenin)expression,decrease cell proliferation associated protein(PCNA,Cyclin D1)levels,promote anti-apoptosis protein(Survivin)levels,reduce monocytes infiltration and limit tumor volume.Conclusions: Low dose CADPE can significantly prevent the occurrence of CRC,and is better than sodium butyrate.CADPE and aspirin have different efficacy characteristics.In particular,CADPE has a significant therapeutic effect on the formation of CRC.The study shows that CADPE can inhibit CRC occurrence and development from tumor cells and inflammatory microenvironment in two aspects with multiple ways(including inhibition of tumor cell proliferation and induced cell death),and execute CRC prevention and treation.