Mechanism of telomerase inhibition by aminosteroid U73122 and related compounds

• Main Authors: Chen yi jui, 陳怡瑞
• Other Authors: 王子堅
• Format: Others
• Language: zh-TW
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/67240286579362099242

碩士 === 長庚大學 === 基礎醫學研究所 === 93 === Telomerase activity is repressed in normal human somatic cells, but is activated in most cancers, suggesting that telomerase may be an important target for cancer therapy. Inhibition of telomerase in cancer cells is anticipated to result in telomere erosion, leading to growth arrest, senescence or cell death. In this study, we report that U73122, an amphiphilic alkylating agent that is known to inhibit phospholipase C, is also a potent inhibitor of human telomerase. No detectable inhibition of telomerase was observed for U73343, the structural analog of U73122, indicating that the inhibitory effect was attributed to the pyrrole-2,5- dione group. Indeed, we observed that 1-ethyl-1H-pyrrole-2,5,-dione（N-ethyl- maleimide or NEM）, but not N-ethylsuccinimide, is an even more potent inhibitor of human telomerase. The IC50 of U73122 and NEM for the in vitro inhibition of telomerase activity were 0.2μM and 5 nM, respectively. The inhibitory action of these drugs on telomerase is selective since the presence of externally added proteins did not protect the inhibition, and all of the other enzymes tested in this study were not inhibited by these drugs at the 5-10X concentrations of the IC50. The inhibitory effect of these drugs may be protected by the presence of thiol- containing compound dithiothreitol, suggesting that these drugs alkylate the cysteine residues of telomerase proteins and thus inactivate the enzyme activity. The potential use of these drugs as telomerase inhibitors for cancers were tested with several cancer cell lines in culture. While these drugs can inactivate telomerase, significant cytotoxicity was frequently observed in the treated cancer cells. At present, it is not yet known whether the observed cytotoxic effect by these drugs is related to the inhibition of telomerase, and therefore, may be selective to cancer cells only