Targeting cancer stem cell by small molecular compounds in esophageal cancer

Abstract

Esophageal cancer is a common and fatal malignancy Squamous cell carcinoma is the predominant histological tumor type in Taiwan Even after surgery and/or concurrent chemoradiation therapy (CCRT) 5-year survival rate of patients is less than 25% Recently there are more evidences showing CCRT-resistance in ESCC patients One possible reason is because of cancer stem cells (CSCs) which have the characteristic of drug-resistance and lead to tumor relapse Previous studies report that CSCs are responsible for tumor initiation progression and metastasis in different cancers In this study we aimed to investigate novel compounds or defined compounds targeting CSCs in ESCC First we established the CSCs culture system which enriched CSCs in the tumor sphere of ESCC cell lines CSCs were treated with novel compounds and their viabilities were determined by WST-1 assay The results demonstrated that NCKU-1501 an ILK (integrin-link kinase) inhibitor had a potency for targeting ESCC CSCs and non-CSCs from drug screening Functional assays showed that NCKU-1501 increased the CCRT response of ESCC cell lines Moreover NCKU-1501 inhibited ESCC tumor sphere formation through down-regulating the stemness- and drug-resistance-associated genes expression In addition we used Connectivity Map to predict compounds which were able to convert CSCs specific genes expression to the levels of ESCC non-CSCs cell lines NCKU-1507 vitamin B derivative didn’t directly inhibit cell viability but it suppressed the tumor sphere formation via down-regulating stemness- and drug-resistance-associated genes expression Interestingly NCKU-1507 could increase the cisplatin sensitivity of the ESCC tumor sphere In conclusion NCKU-1501 may be a potential therapeutic compound targeting ESCC CSCs NCKU-1507 may reverse ESCC CSCs specific gene expression and increase ESCC sensitivity to cisplatin

Date of Award	2014 Aug 28
Original language	English
Supervisor	Pei-Jung Lu (Supervisor)