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標題: Niclosamide 經由Src途徑抑制乳癌細胞生長
Niclosamide inhibits breast cancer progression through Src pathway
作者: 林金瑤
Lin, Chin-Yao
Contributors: 陳健尉
生命科學院碩士在職專班
關鍵字: 乳癌;Src;Src抑制劑;dasatinib;耐克螺
Breast cancer;Src;Src inhibitor;dasatinib;niclosamide
日期: 2013
Issue Date: 2013-11-07 13:05:58 (UTC+8)
Publisher: 生命科學院碩士在職專班
摘要: 三陰性乳癌(triple negative breast cancer)一般認為是乳癌中病程進展較快的亞型,有較高比例造成局部復發、遠端器官的轉移及死亡。這類患者對化學治療的反應比較好,但是主要的全身性治療也只有化學治療。找出新的藥物若能增加化學治療的效果,以減少三陰性乳癌患者的復發或轉移是必要的。Src是一種酪氨酸激酶,屬於Src酪氨酸激酶家族(Src family kinases; SFKs)的一員,能調節多個與酪氨酸激酶相關的細胞膜間接受體誘使細胞內標靶蛋白的活化,包括PI3-kinase, focal adhesion kinase (FAK)及signal transducers and activators of transcription 3 (Stat3)。在多項癌症研究中發現,當Src路徑被活化可能促進癌細胞增生、存活、分化、移動及侵犯等。乳癌的研究發現表皮生長因子接受體(Epidermal Growth Factor Receptor; EGFR)會活化及增加Src的活性,在乳癌合併骨頭轉移的患者,Src的表現也代表較差的預後。因此,抑制Src的藥物可能對於乳癌的治療有所幫助。單獨使用Src抑制劑Dasatinib或Bosutinib在乳癌的治療效果並不理想。本實驗室發現耐克螺(niclosamide)可以抑制Src活性及肺癌細胞存活能力,並誘導細胞凋亡,推測耐克螺可能是具有臨床治療潛力的Src抑制劑。耐克螺是一種口服的驅蟲藥,主要使用於絛蟲感染的患者,研究發現,耐克螺可以抑制癌細胞的增生、遷移及侵襲。我們發現在耐克螺處理72 小時後,細胞的存活率隨著藥物濃度顯著降低。此外,表皮生長因子接受體、磷酸化的FAK、FAK、磷酸化的Stat-3和Stat-3的活性皆被抑制。耐克螺可抑制細胞遷移,侵襲和聚落形成。我們的研究顯示,耐克螺可能經由Src的途徑抑制乳癌的進展。在未來,化學治療合併耐克螺治療可能是乳癌治療的選項,尤其是在三陰性乳腺癌患者。
Triple negative breast cancer is generally considered the rapid progression of breast cancer subtype, resulting in a higher propotion of local recurrence, distant metastasis and death. These patients are sensitive to chemotherapy, but the main systemic therapy of them is only the chemotherapy. It is necessary to find new drugs to increase the effects of chemotherapy to reduce recurrence or metastasis of triple negative breast cancer. Src is a tyrosine kinase, and belongs to Src family kinases (SFKs). SFKs regulate signaling from multiple transmembrane receptor-associated tyrosine kinases and lead to activation of intracellular target proteins including PI3-kinase, focal adhesion kinase (FAK) and signal transducers and activators of transcription 3 (Stat3). In a number of various cancer studies, they found that the activation of Src pathway promotes cancer cell proliferation, survival, differentiation, migration and invasion. EGFR activates Src and also increases the activity of Src in breast cancer research. In breast cancer patient with bone metastasis, expression of the Src also represents a poor prognosis. Therefore, Src inhibitor maybe helpful for the treatment of breast cancer. Src inhibitor, Dasatinib or Bosutinib, use alone in breast cancer treatment is not ideal. Our lab found that niclosamide can inhibit activity of Src and lung cancer cell viability and induction of apoptosis, suggesting that niclosamide may have clinical potential and serve as a Src inhibitor. Niclosamide is an oral anthelmintic, mainly used in tapeworm infected patients, our study found that niclosamide can inhibit cancer cell proliferation, migration and invasion. We found that treated cancer cells with Niclosamide for 72 hours, the cell viability reduced significantly and in a concentration-dependent manner. In addition, the activity of EGFR, phospho-FAK, FAK, phospho-Stat-3 and Stat-3 were to be suppressed. The treatment with Niclosamide significantly increased the apoptosis. Furthermore, the effects of niclosamide may inhibit cell migration, invasion and colony formation. Our research shows that niclosamide might inhibit breast cancer progression through Src suppression pathway. In the future, combined chemotherapy with niclosamide may be considered beneficial for breast cancer treatment, especially in triple negative breast cancer patients.
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