Identification of old drugs with selective toxic effects on human colon cancer stem cells using Connectivity map

• Main Authors: Hsin-Yu Tsou, 鄒心榆
• Other Authors: Yeu Su
• Format: Others
• Language: zh-TW
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/2b672s

碩士 === 國立陽明大學 === 生物藥學研究所 === 102 === Cancer stem cells (CSCs) have been widely postulated to play crucial roles in the initiation, distant metastasis, recurrence and drug resistance of most cancers including colorectal carcinoma (CRC). Hence, to improve the efficacy of current treatments for this malignancy, it is essential to eradicate this subpopulation (colorectal cancer stem cells, CRSCs) together with tumor mass. In order to achieve this goal more effectively, the Connectivity Map (CMap) was employed to search for some already-been used drugs that could target specifically CRSCs. With this respect, I postulated that drugs capable of reversing at least partially the gene expression profiles of CRSCs might be investigation. After CMap analysis and extensive literature search, the cytotoxic effects of 13 drugs including amiloride (Aml), amiodarone (Amd), apigenine (Apg), ciclopirox (Cic), clioquinol (Cli), dipyridamole (Dip), gossypol (Gos), harmine (Har), mefloquine (Mef), omeprazole (Ome), pargyline (Par), pyrvinium (Pyv) and tretinoin (Tre) on 3 human CRC lines, HT-29, HCT-15 and HCT-116, were evaluated. The ones with IC50 ≤ 40 μM (Amd, Cic, Cli, Gos, Har, Mef and Pyv) were subsequently assessed for their efficacies in diminishing CRSC subpopulation. To our surprise, none of these candidates could decrease the CD44+ subpopulation in HCT-15 cells. On the other hand, Cli, Gos and Mef reduced the CD44+/CD133+ subpopulations in both HT-29 and HCT-116 cells. In addition, these drugs further inhibited the sphere-forming abilities of two cell lines, suggesting that three candidates suppressed self-renewal of the stem cell subpopulations in both H-T29 and HCT-116 lines. Surprisingly, treatment of HT-29 cells with Cli and Mef only reduced mRNA levels of CD44 and Lgr5 significantly. However, only Cli effectively reduced Lgr5 protein levels. Collectively, my results suggest that clioquinol and mefloquine are worthy of detailed examination for their potential anti-CRSC activities.