喹唑啉酮類緣物引發人類皮膚癌細胞有絲分裂災變機制之探討; Investigation of the mechanisms of quinazolinone analog-induced mitotic catastrophe in human skin cancer cells

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题名:	喹唑啉酮類緣物引發人類皮膚癌細胞有絲分裂災變機制之探討;Investigation of the mechanisms of quinazolinone analog-induced mitotic catastrophe in human skin cancer cells
作者:	劉文治;Wen-Zhi Liu
贡献者:	中國醫藥大學：藥學系碩士班
关键词:	喹;唑啉;酮;皮膚癌;有絲分裂災變;細胞週期;細胞骨架;quinazolinones;skin cancer;mitotic catastrophe;cell cycle;cytoskeleton
日期:	2009-06-19
上传时间:	2009-08-13 10:54:01 (UTC+8)
摘要:	微小管在細胞的有絲分裂中對於紡錘絲的形成及染色體的分離扮演著重要的角色，已有許多文獻指出影響微小管形成的藥物可有效的抑制癌細胞的生長。喹唑啉酮類生物鹼是芸香科（Rutaceae）植物中所含的活性成分，雖然已有許多研究者証實喹唑啉酮類緣物具有抗癌活性，然而，其真正的抗癌作用機制仍然未被釐清。2-(Naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone（HL66）是合成的喹唑啉酮類緣物。在本實驗的抗癌活性篩選研究中，我們發現HL66對皮膚癌（M21）、肺癌（CH27及H460）、肝癌（Hep3B）及口腔癌（HSC-3）細胞株具有優異的抗癌活性，而其中HL66對皮膚癌細胞的抗癌活性最佳。在本研究中，我們証實HL66引起皮膚癌M21細胞死亡並不是典型的細胞凋亡，而是屬於有絲分裂災變的細胞死亡。在HL66誘導M21細胞有絲分裂災變的死亡中，因HL66引起染色體不正常分離而形成不規則形的細胞核及具有多核的巨形細胞的有絲分裂災變的典型特徵。我們也証實HL66是經由抑制微小管的形成而導致M21細胞細胞週期停滯在S phase與G2/M phase。除此之外，HL66經由caspase-independent途徑誘導的有絲分裂災變的死亡過程中也伴隨著Bcl-2蛋白磷酸化及大量的cyclin B1聚集於細胞核等現象的發生。我們也發現HL66抑制Cdk1之Thr14與Tyr15的解磷酸化及Cdk1/cyclin B1複合物的形成，而使細胞週期無法從有絲分裂期的前期進入中期。此外，HL66引起M21細胞死亡與在細胞週期中調控G1/S phase（cyclin A、D及E；Cdk2及4）及G2/M phase（cyclin B1及Cdk1）的蛋白分子異常表現有關。綜合以上結果，我們証實HL66是一個微小管形成的抑制劑，因此，我們期待HL66可以被開發成新的抗癌藥物。 Microtubules are a proven target for anticancer drug development because they are critical for mitotic spindle formation and the separation of chromosomes at mitosis. Quinazolinone alkaloids are the active components contained in the plants of Rutaceae. Many investigators have indicated that quinazolinones have anti-tumor activity. However, the reasons why the molecular mechanisms of quinazolinones produced their biological effects remain unknown. In our study, the screening test for anti-tumor activity of quinazolinone derivatives has demonstrated that HL66 displayed anti-proliferation in several cancer cell types, especially for skin cancer M21 cells. We here report a novel synthetic anti-microtubule agent 2-(naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone (HL66), a quinazolinone analog. The data presented in this report show that the HL66-induced cell death in M21 cells that was resistant to apoptosis, we identified mitotic catastrophe with characteristics of abnormal chromosome segregation, irregular nuclei and large cells with multiple micronuclei. We also demonstrate that HL66 is a tubulin-destabilizing agent and causes cell cycle arrest at S and G2/M phase. In addition, HL66-induced M21 cell mitotic catastrophe was caspase-independent and accompanied by the phosphorylation of Bcl-2 and translocation of cyclin B1 to nucleus. Results demonstrated that HL66 inhibits the dephosphorylation on Thr14 or Tyr15 of Cdk1 and the formation of Cdk1/cyclin B1 complex, leading to the failure of the progression of cell cycle from prophase to metaphase. Furthermore, our data show that the aberrant expression of the cell cycle regulatory molecules of G1/S (cyclin D1/Cdk4; cyclin A or E/Cdk2) and G2/M (Cdk1/cyclin B1) phase may lead to abnormal cell cycle during HL66-induced M21 cell mitotic catastrophe. Taken together, these results describe a novel pharmacological property of HL66 as a microtubule inhibitor, which may make it an attractive new agent for treatment of cancer.
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