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題名 | 惡性腫瘤之粒線體異常與應用癌細胞粒線體為標靶之化學治療策略的發展=Alterations of Mitochondria in Tumors and Recent Advances in the Development of Mitochondria-targeting Chemotherapy |
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作者姓名(中文) | 洪文怡; 李新城; 魏耀揮; | 書刊名 | 化學 |
卷期 | 64:4 民95.12 |
頁次 | 頁435-449 |
分類號 | 368.65 |
關鍵詞 | 抗癌藥物; 細胞凋亡; 化學治療; 粒線體; 粒線體DNA; 粒線體標定藥物; Anticancer drug; Apoptosis; Chemotherapy; Mitochondria; Mitochondrial DNA; Mitochondria-targeting agents; |
語文 | 中文(Chinese) |
中文摘要 | 臨床上常用的化學療法經常面臨無法選擇性傷害腫瘤細胞以及克服抗藥性的阻礙而影響其治療效果,因此以腫瘤細胞與正常細胞代謝之顯著差異作為藥物作用標的是改善傳統治癌策略的必要對策。粒線體於細胞中扮演相當重要的生理調控角色,不但負責檸檬酸循環與脂肪酸代謝反應,進行呼吸與氧化磷酸化作用以合成ATP ,同時也參與細胞凋亡之調控與執行。除了身兼供給能量及決定細胞生死的角色,粒線體於腫瘤細胞的生長發展過程中也有重要的影響。早在1930 年代,Otto Warburg即發現粒線體功能缺陷可能與癌症的發生有關,並可能是造成腫瘤細胞糖解作用增加的原因。最近十幾年來,由人類各種腫瘤組織的研究,科學家已經發現其粒線體DNA 具有較高的突變率以及部份腫瘤含有較低的粒線體DNA拷貝數。由於粒線體DNA的完整性影響著粒線體呼吸酵素的表現及功能,因此其變異可能造成腫瘤細胞中粒線體呼吸酵素之功能異常。另外,腫瘤細胞中由細胞核DNA 所表現的粒線體呼吸及代謝相關酵素如succinate dehydrogenase (SDH)及主要負責調控粒線體膜通透性的Bcl-2 superfamily 與由多個粒線體蛋白組成的粒線體膜通透孔洞(mitochondrial permeability transition pore, MPTP)也被發現有異常的狀況。這些變異將導致腫瘤細胞無法在一般生理情況下進行細胞凋亡以及對部分化療藥物產生抗藥性。利用腫瘤細胞與正常細胞中粒線體在質與量上的顯著差異,以粒線體作為抗癌藥物作用的標的將具有發展潛力。近年來陸續有許多具抗癌效用之粒線體標定化合物被發表,部分甚至已進入臨床試驗階段。因此,本文將簡述腫瘤細胞中粒線體及粒線體DNA的變異情形,以及針對各具潛力之粒線體作用點,分類說明目前已開發或正在開發中之粒線體標定化合物的抗癌機制及臨床應用。 |
英文摘要 | The therapeutic efficiency of conventional cancer chemotherapies is often hampered by their poor tumor cell-selectivity and the drug resistance developed in most tumor cells. To improve the clinical outcome of cancer chemotherapy, it is a practical strategy to use the differences in metabolic characteristics of mitochondria between tumor and normal cells as drug targets. Mitochondria play key roles in the oxidative metabolism of tricarboxylic acids and fatty acids for energy production to support normal function and act as an arbitrator in the initiation and execution of apoptosis of mammalian cells. In the early 1930s, Otto Warburg put forward a hypothesis that defective mitochondrial function is involved in tumorigenesis, and that tumor cells would thus rely more on glycolysis for energy supply. This proposal first raised the possibility that mitochondria play a role in tumor progression. In the past decade, it has been established that tumor cells usually have higher rate of mitochondrial DNA (mtDNA) mutation and that some cancers have lower mtDNA content. Moreover, some of the nuclear DNA-encoded mitochondrial proteins such as succinate dehydrogenase (SDH), Bcl-2 superfamily and mitochondrial permeability transition pore (MPTP) proteins have been found to be mutated in several kinds of human cancers. The alterations in the structure or function of these proteins might prevent tumor cells from apoptosis under normal conditions and lead to the development of drug resistance to anticancer agents that induce apoptosis. Therefore, it holds great promise to develop anticancer drugs targeting at mitochondria. In recent years, many mitochondria-targeting compounds with anticancer activities have been developed, and some of them have entered clinical trials. In this review, we discuss various alterations in mitochondria and mtDNA occurring in tumors and the potential in the development of mitochondria-targeting agents for cancer chemotherapy. |
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