辣椒素在人類口腔癌Kb細胞經由凋亡蛋白酶路徑誘導細胞凋亡

Capsaicin induce apoptosis in human oral cancer Kb cells through the caspase pathway

王哲偉(Che-Wei Wang)

指導教授 ： 張文正

長榮大學/健康科學學院/醫學研究所/碩士(2010年)

摘要

口腔癌每年在臺灣都有增多的趨勢。其最主要是以手術方式去治療，而放射線治療及同步放射線併化學藥物治療主要是對於較進展性的口腔癌患者。目前治療口腔癌化學治療藥物的發展有朝向天然植物方面的萃取，例如紫彬醇化學治療藥物是從天然植物紫杉分離得來。
為了明瞭天然植物的化學治療效用，而辣椒素(Capsaican)是存在於辣椒屬中多種不同紅辣椒植物的主要刺激性成分,屬於vaniloid成員之一。在許多研究中指出辣椒素對許多癌細胞株(例如肝癌.子宮頸癌及食道癌等)均具有生物活性,能抑制細胞生長。然而辣椒素在人類口腔癌細胞所引發的細胞凋亡機轉並不很清楚，因此我們的這個研究主要是探討辣椒素在人類口腔癌細胞Kb cells所造成細胞凋亡的可能性及機轉。
細胞凋亡，是細胞進行有計劃性死亡的一個重要環節，和腫瘤細胞是互相抵觸的。在各種不同抗腫瘤藥物作用下會使得腫瘤細胞走向凋亡的路徑，而細胞凋亡的路徑主要分為兩步驟即外生性及內生性的途徑；外生性路徑開姑於由結合子活化死亡接受體，然後死亡接受體引發死亡訊息複合體，促使凋亡蛋白8活化(caspase-8)進而活化凋亡蛋白3,6,7而導致細胞凋亡，外生性路徑也與非依賴受體經介質活化凋亡蛋白3,6,7促進者而導致細胞凋亡；內生性路徑開始於細胞內訊息例如DNA破壞和內質網壓力使得粒線體膜電位被消除而釋放出原始細胞凋亡因子例如Cytochrome c而Cytochrome c促使APAF-1和ATP/dATP形成apoptosome去活化凋亡蛋白9，進而活化凋亡蛋白3,6,7而導致細胞凋亡。凋亡蛋白3,6,7裂解caspase-activated DNAase抑制體，導至產生PARP的180-bp DNA碎片。
抗腫瘤的特性主要生化的作用是阻斷細胞周期的進展和誘發腫瘤細胞走向細胞凋亡，細胞周期的停止和細胞凋亡的產生在抗腫瘤作用是一個有意義的指標；因此我們研究辣椒素作用在口腔癌KB 細胞上所導至細胞週期停止及細胞凋亡的現象，辣椒素具有成為口腔癌治療藥物的潛力。

關鍵字

辣椒素 ； 口腔癌Kb細胞 ； 凋亡蛋白酶細胞凋亡

並列摘要

Oral cancer has increased more and more per year in Taiwan. One of the main therapeutic maneuver is to operate surgery. Radiotherapy, and even concurrent radiochemotherapy will be given for the patients with advanced oral cancer. Now chemotherapy drugs extracted from the natural plants are developed to treat oral cancer. Docetaxol is isolated from a native plant, Yew.
To gain insight into the effect of chemotherapy drugs from natural plant, Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a major pungent ingredient in variety of red peppers of the genus Capsicum, is a type of vanilloid. It has been shown a biological activities on various human cancer cell lines. However, the mechanism by Capsaicin which induces apoptosis in human oral cancer is unknown. Therefore we will study the probability and the mechanism of apoptosis in KB cells induced by Capsaicin.
Apoptosis, one type of programmed cell death (PCD), is the best-defined cell death program counteracting tumor growth. Apoptosis induces cell death in tumor treated with various anti-cancer drugs. Apoptosis has been divided into two pathways definitely: extrinsic and intrinsic pathways. The extrinsic pathway begins by death receptors, which were activated by ligands. Death receptors induces the assembly of death-inducing signaling complex, which promotes the activation of caspase-8 (and -10 possibly), which activates the effector of caspase-3, -6, and -7. Then they lead to apoptosis. The extrinsic pathway also involves dependency receptors, which were activated in the absence of ligands through unidentified mediators to activate the effector of caspase-3, -6, and -7. The intrinsic pathway begins by intracellular signals, including DNA damage and endoplasmic reticulum stress, which converge on mitochondria to dissipate transmembrane potential of mitochondrial membrane permeability (MMP), which releases proapoptotic factors, including cytochrome c, from intermembrane space. Cytochrome c induces apoptosis protease-activating factor 1 (APAF-1) and ATP/dATP to assemble apoptosome, which activates caspase-9, which activates the effector of caspase-3, -6, and -7. Then they lead to apoptosis. Caspase-3, -6, and -7 cleaves an inhibitor of caspase-activated DNAase and produces poly-(ADP-ribose) polymerase (PARP), which results in ~180-bp DNA fragmentation.
In addition, the majority of biochemicals has been reported to exert anti-cancer property by blocking cell cycle progression and triggering tumor cell apoptosis. Cell cycle arrest and apoptotic induction in tumor cells become significant indicators of anti-cancer effect. Therefore we will study what cell cycle arrest when apoptosis in KB cells is induced by Capsaicin. Hence, Capsaicin may be a potent drug in oral cancer therapy.

並列關鍵字

capsaicin ； human oral cancer Kb cells ； caspase ； apoptosis

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