Targeting cancer stem cell by small molecular compounds in esophageal cancer

• Main Authors: Wan-ChunHung, 洪琬珺
• Other Authors: Pei-Jung Lu
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/6p8uvh

碩士 === 國立成功大學 === 臨床醫學研究所 === 102 === 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.