| Objective: Colorectal cancer(CRC)is one of the most common cancers worldwide.The incidence rate of CRC in China has been increasing significantly in the last 5 to10?years,largely attributed to dietary changes,an aging population,and environment pollution.Surgical resection remains the best treatment for colorectal cancer therapy.However,approximately 20-25% of CRC patients are diagnosed as stage IV disease and have distant metastases,and another 25% will develop metastases in the follow-up period.Treatments for advanced stage III and IV CRC are still limited.When untreated,patients with metastases have a median survival of 6-9 months.Pharmacotherapy plays a key role in colorectal cancer therapy and metastasis inhibition.Although significant clinical benefits has been found with the application of cetuximab and bevacizumab in combination with chemotherapy,the morbidity and mortality of CRC is still high due to drug resistance and side effects.Therefore,it is urgent to develop novel,effective and less toxic drugs.Thymol is a phenolic compound that is recognized as safe for use in food as well as medical and cosmetic fields.Increasing evidence has indicated that thymol exerts prominent antitumor effects in a variety of cancers.However,how thymol elicits these effects on CRC and the associated underlying mechanisms remains unclear.Methods:Thymol was isolated and extracted from Thymus vulgaris L..HCT116 and Lovo cells were treated with different concentrations of thymol.Cell counting kit-8(CCK-8)and transwell migration and invasion assays were used to evaluate cell proliferation,migration,and invasion,respectively.Cell apoptosis and cell cycle distribution were measured by flow cytometry.Overexpression of ?-catenin(?-catenin)cell lines and knockdown of ?-catenin(si-?-catenin)cell lines were constructed by plasmids and small interfering RNA transfection method in CRC HCT116 and Lovo cells.The functional experiments including cell proliferation,migration and invasion were carried out by cell counting kit-8 assay and transwell assay to confirm the role of ?-catenin in the treatment of thymol on colorectal cancer.Xenograft nude mice model and haemotogenous dissemination model were established and tumor volume and metastases were quantified.q RT-q PCR,western blot,and immunohistochemistry were used to detect the expression of related genes and their protein products.Results:In this study,we tested the antitumor activity of thymol extracted from a Chinese medicinal herb,Thymus vulgaris L.We show that thymol treatment in vitro inhibited cell proliferation and induced apoptosis and cell cycle arrest in CRC.Thymol administration induced CRC cell apoptosis through activation of the Bax/Bcl-2signaling pathway.In addition,thymol suppressed CRC cell proliferation,migration,invasion,and epithelial-mesenchymal transition(EMT)via inhibiting the activation of the Wnt/?-catenin pathway.Overexpression of ?-catenin abolished the inhibitory effect of thymol on cell proliferation,invasion,and migration,on the contrary,cotreatment with thymol and ?-catenin si RNA synergistically inhibited cell proliferation,invasion,and migration.Furthermore,in xenograft nude mice model,treatment with 75 and 150 mg/kg thymol led to a significant decrease in tumor volume.In metastatic nude mouse model,thymol suppresses lung metastasis of HCT116 cells.Conclusions: Thymol can inhibit CRC cells proliferation and block effectively HCT116 and Lovo cells in the G0/G1 phase.Thymol can induce CRC cell apoptosis through activation of the Bax/Bcl-2 signaling pathway.Thymol decrease CRC cells migration and invasion ability through the regulation of EMT.In vivo thymol can inhibit the growth of subcutaneous xenografl and reduce colorectal cancer cell lung metastasis.Thymol may prevent CRC progression through inhibition of the Wnt/?-catenin signaling pathway,highlighting its potential as a novel therapeutic option for the treatment of CRC. |
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