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標題: | 三磷酸腺苷對於Doxorubicin的抗腫瘤活性之調節 Modulatory effect of ATP on doxorubicin-mediated antitumor activity |
作者: | Yeo-Loo Chang 張佑如 |
指導教授: | 林琬琬 |
關鍵字: | 三磷酸腺苷,肺癌, ATP,Doxorubicin,lung cancer, |
出版年 : | 2010 |
學位: | 碩士 |
摘要: | 此實驗中,我們探討三磷酸腺苷(ATP)對於doxorubicin在二株肺癌細胞CL1.0及CL1.5的細胞毒性之影響。這兩株肺癌細胞株的最大不同點是CL1.5相較於CL1.0是具有高度轉移能力及抗藥性。我們利用doxorubicin測試細胞毒性證實CL1.0的確對doxorubicin有高敏感性。但不論對doxorubicin的敏感性為何,外給ATP均會抑制doxorubicin對CL1.0及CL1.5所引發的細胞死亡。實驗結果顯示ATP會減弱doxorubicin對於CL1.0細胞所造成的細胞凋亡及細胞壞死現象,如會抑制sub-G1 peak的產生、caspase 3 的活化、propidium iodide 的吸收、及活性氧化物的產生。此外ATP亦可抑制doxorubicin所誘發的p53累積及活化。同時給予p53抑制劑pifithrin-α時會抑制doxorubicin的毒性,而此情況下ATP的保護細胞效果降低,顯示p53在ATP的保護作用中扮演一個重要的角色。同時,活性氧化物清除者(ROS scavenger) N-acetylcysteine亦可保護doxorubicin引起的細胞死亡、p53的累積及PAR的產生。此外,我們發現在同時給予ATP的情況下,相較於只有doxorubicin處理的組別,會更增加NF-κB的活性。其他嘌呤核苷酸,例如UTP,UDP及ADP也會抑制doxorubicin的抗腫瘤活性。然而,ATP不會保護其他具有細胞毒性的藥物所造成的細胞死亡,且ATP保護CL1.0細胞的作用在其他的癌細胞,如PC3及HeLa細胞中是看不到的。總括而言,雖然doxorubicin在CL1.0及CL1.5兩株細胞有不同的敏感性,但ATP同樣具有對抗其細胞毒性的作用。降低活性氧化物的產生、DNA的傷害、p53及caspase 3活化,及促進NF-κB活化均貢獻於ATP保護肺癌細胞株免受doxorubicin的毒殺作用。 In the present study, we investigated the effect of ATP on the cytotoxicity of doxorubicin in two lung cancer cell lines, CL1.0 and CL1.5. The major difference of both cell lines is that CL1.0 is nonmetastatic, while CL1.5 is highly metastatic. Here, we confirmed that CL1.5 cells are more resistant to doxorubicin (DXR) as compared to CL1.0 cells, and found exogenous ATP can protect DXR-induced cell death in both cell lines. Both apoptosis (characterized by sub-G1 peak, caspase 3 activation) and necrosis (characterized by propidium iodide uptake and ROS production) features induced by DXR in CL1.0 were reduced by ATP. In addition, ATP can inhibit p53 accumulation and phosphorylation under DXR treatment. The cytotoxicity of DXR was diminished by the treatment with p53 inhibitor pifithrin-α, indicating the role of p53 in the anti-tumor action of DXR. Moreover, ROS scavenger N-acetylcysteine protected cell death, p53 accumulation and PAR formation induced by DXR. Besides, we found that combination treatment with ATP enhanced more NF-κB activation compared to DXR treatment alone. Other purinergic nucleotides, such as UTP, UDP and ADP, also diminished the antitumor activity of DXR in CL1.0. However, we found such cytoprotective effect of ATP was neither observed for other cytotoxic agents in CL1.0 cells or even for DXR action in PC3 prostate and HeLa cervical cancer cell lines. In summary, even though DXR has differential anti-tumor sensitivity in CL1.0 and CL1.5 lung cancer cells, ATP can protect both cell lines against DXR-induced cell death. Attenuation of ROS production, DNA damage, p53 and caspase activation, as well as the increase in NF-κB activation might all contribute to the cytoprotective effect of ATP on DXR-induced mixed type of cell death in CL1.0. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/47067 |
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顯示於系所單位: | 藥理學科所 |
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