2010-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658495摘要：Gleevec (ST1571, imatinib mesylate)，是用來拮抗Bcr-Abl 酪胺酸激酶作用的抑制劑；它是第一個利用標靶分子Bcr-Abl 設計並已成功的有效用於治療慢性骨髓性白血病人(CML)的藥物。 Gleevec 除了會抑制 Bcr-Abl 的酵素活性之外，也能抑制c-Abl 的酵素作用；c-Abl酪胺酸激酶會依照它位於胞內的不同部位，產生不同的作用來調控複雜的細胞生長或死亡的訊息傳導。一般c-Abl 酪胺酸激酶若位於細胞質會有增進細胞生長存活的作用;相反，若位於細胞核則有增進細胞死亡的作用。因此Gleevec 除對慢性骨髓性白血病有療效外，是否對不同種類的腫瘤細胞具有毒殺作用，以及在其惡化機轉中所扮演的角色是有趣並值得進一步探討的課題。過去關於TRAIL 的研究顯示，TRAIL 會選擇性地誘發腫瘤細胞的死亡, 而對正常組織細胞則無明顯的毒性,因此是開發中的抗癌藥物。為確立TRAIL 合併用藥的有效性及擴展Gleevec 在抗癌的新用途，我們將探討Gleevec 對TRAIL所誘發的各種癌症細胞死亡機制上的影響。我們初步的研究顯示，Gleevec 協同TRAIL 的作用會對K562 白血病細胞具有加成性的毒性效果。但令人驚訝的是，在兩種人類的結腸癌細胞株 (HCT116 和 SW480)的實驗中，Gleevec 會降低TRAIL 所造成的細胞毒性。而且，我們也發現在Gleevec 所造成的保護結腸癌細胞死亡機制中，JNK 和 p 38 的作用會受到抑制。依據這些初步的研究結果，這一個計畫的研究目標將包括 (1) 釐清在各種不同的癌症細胞中，Gleevec 和TRAIL 的合併用藥對癌細胞凋亡的影響。(2) 確立在Gleevec 和TRAIL 的合併藥物作用(不論是拮抗性或是加成性)的細胞死亡機制中，由Caspase(外生性)和由粒線體(內生性)所主導的兩種細胞凋亡路徑所扮演的角色。(3)我們也將進一步去了解 c-Abl 的活化在TRAIL所主導的細胞毒性中的重要性。(4)由於p53 和 p73 已被發現是c-Abl 造成調控細胞死亡的訊息傳導路徑下游的兩個重要分子，我們也將探討在不同的癌症細胞中p53 和 p73對 Gleevec 和TRAIL 合併用藥所造成細胞死亡結果中所扮演的角色。我們相信這個研究計畫藉由探究TRAIL 和 Gleevec 合併藥物作用以及訊息傳遞的交互作用，對評估Gleevec 是否能與TRAIL 合併運用作為其他腫瘤用藥的潛力可提供更有利的支持與了解。而且，分子層級的分析也將開啟c-Abl 和caspase 所主導的細胞凋亡路徑的交互作用的新視野。<br> Abstract: Gleevec (ST1571, imatinib mesylate), a tyrosine kinase inhibitor against Bcr-Abl,exemplifies the successful development of a rationally designed, molecularly targeted therapyfor the treatment of chronic myelogenous leukemia (CML). In addition to inhibit Bcr-Abl,gleevec also can inhibit c-Abl, which depending on subcellular localization and regulatingsignal network possesses multiple functions in cell growth and death. The use of gleevec withdifferent tumors and the translation of this paradigm to other malignancies are still interestingto explore. TRAIL has been shown to selectively induce tumor cell death, and has minimaltoxicity against normal tissues. In seeking to develop combination validity of TRAIL, weelucidate the effects of gleevec in TRAIL-induced cancer cell death. Our preliminary studyconfirms the synergistic toxicity between gleevec and TRAIL in K562 leukemia cells.Surprisingly TRAIL induced cytotoxicity in two human colon cancer cell lines (HCT116 andSW480) is reduced by gleevec. Moreover, we suggest that inhibition of JNK and p38 isinvolved in gleevec-induced protection. Continuing these preliminary findings, the specificaims of this project include (1) to clarify the combinatorial apoptotic effects of gleevec andTRAIL in various cancer cells; (2) to identify the roles of caspase and mitochondria-mediatedapoptotic pathways in the antagonistic and synergistic cell death between gleevec and TRAILin colon cancer and K562 cells, respectively; (3) to understand the role of c-Abl activation inTRAIL-induced cytotoxicity; (4) to dissect the roles of p53 and p73 in the antagonistic andsynergistic cell death between gleevec and TRAIL in colon cancer and K562 cells,respectively. p53 and p73 are two downstream effectors of c-Abl and play crucial roles inregulating cell death. We believe this study exploring the interactive effects and signalinginterplay between TRAIL and gleevec can provide informative evidence to understand ifgleevec may also possess potential to treat some solid tumors. Moreover, molecular analysiswill shed new insight into c-Abl interaction with caspase-dependent apoptotic pathways.TRAILGleevecc-Ablp73p53細胞凋亡TRAILGleevecc-Ablp73p53apoptosis