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研究生:王涵
研究生(外文):Hang Wang
論文名稱:探討營養補充減緩化療及肺癌小鼠惡病質症狀之機制
論文名稱(外文):Study on the mechanisms of attenuation of cachectic symptoms by nutritional intervention after chemotherapy in lung cancer mice
指導教授:吳彰哲
指導教授(外文):Chang-Jer Wu
學位類別:博士
校院名稱:國立臺灣海洋大學
系所名稱:食品科學系
學門:農業科學學門
學類:食品科學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:143
中文關鍵詞:肺癌惡病質肌肉萎縮化療
外文關鍵詞:lung cancercachexiamuscle atrophychemotherapy
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癌症惡病質為一種惡性衰弱的病症,惡病質顯著提高癌症患者的發病率及死亡率。其中,免疫受損及肌肉流失為惡病質主要的症狀,其會導致一連串的嚴重後果。除了找尋新的治療藥物及策略,找尋導致這些問題的因子及機制也為目前刻不容緩的課題。本論文首先建立鼠類肺癌及其化療藥物誘導之惡病質模式,包含了顯著的體重流失、慢性發炎及異常的免疫功能等惡病質症狀。腫瘤誘導惡病質模式之結果發現,腫瘤背負小鼠脾臟中Tregs及MDSC的增加與腫瘤生長呈現正相關性。另外,骨骼肌肉的萎縮主要是由於TNF-alpha及myostatin的大量表現,進而正調控calcium-activated及ubiquitin-proteasome系統。然而,腫瘤背負小鼠在服用魚油及酵母硒後,可顯著降低Tregs及MDSC之細胞數目,進而提高抗腫瘤之免疫力,且減緩體重、肌肉及脂肪的流失。此外,此兩種營養素合併使用具有加乘效果。另一個具抗惡病質潛力之營養素為 (-)-Epigallocatechin-3-gallate (EGCG) 則是可調控腫瘤背負小鼠肌肉中NF-kB及其下游因子ubiquitin ligases (MuRF-1及MAFbX) 之表現量。正常小鼠施打化療藥物docetaxel後,發現其會顯著降低肌肉重及脾臟細胞數,且血液中IL-6與IL-1 beta含量增加。然而,我們意外發現利用化療藥物 (例如:docetaxel、cisplatin或5-FU) 治療腫瘤時,可降低腫瘤小鼠脾臟中Tregs及MDSC之細胞數,且不會影響CD4+ T、CD8+ T及NK細胞。儘管如此,化療藥物 (如:docetaxel) 仍表現出增加肌肉萎縮之副作用,包括顯著提高myostatin及其參與的FOXO-1訊息傳遞,進而導致蛋白質分解。為了降低化療藥物導致的副作用,我們利用中草藥複合物 (合併黃芩Scutellaria baicalensis與清暑益氣湯Qing-Shu-Yi-Qi-Tang) 搭配半正常使用劑量的化療藥物5-FU,來探討此策略對抗腫瘤及抗惡病質之效用。結果發現,腫瘤及體重流失均有顯著降低,且可提高Th1/Th2比率及NK細胞毒殺能力。因此,合併黃芩與清暑益氣湯,可以改善腫瘤背負小鼠經化療後所導致的惡病質症狀,且可刺激抗腫瘤之免疫能力。除此之外,經化療之腫瘤背負小鼠在服用合併魚油及酵母硒之營養後,可顯著降低肌肉中IL-6、TNF-alpha及myostatin的表現量,有效的減緩骨骼肌肉的流失及抑制蛋白質分解的相關調控基因。綜合上述結果顯示,魚油合併酵母硒 (營養素複合物)、黃芩合併清暑益氣湯 (中草藥複合物) 及EGCG的介入可以減緩腫瘤或其化學治療所造成的惡病質症狀,如:肌肉蛋白質分解及促進抗腫瘤之免疫能力;因此,上述營養介入之策略具有提升癌症患者的臨床療效之潛力。
Cancer cachexia is a severe debilitating disorder, which causes significant morbidity and mortality. Impaired immune function and muscle wasting are major symptoms for cancer cachexia, leading to serious consequences. In addition to the effort to look for a new therapy and different treatment strategy, the identification of biological factors and mechanisms is of increasing importance. Here, we show that advancement of cachexia in a murine lung tumor or its chemotherapeutic agent-induced cachectic models manifested with such indicative symptoms as weight loss, chronic inflammation and disturbed immune functionality. In several tumor-induced cachectic model, the elevation of Tregs and MDSC in spleens of tumor-bearing mice was positively correlated with tumor burdens. Atrophy of skeletal muscle is due to an overexpression in TNF-alpha and myostatin, leading to up-regulate calcium-activated and ubiquitin-proteasome systems in tumor-bearing mice. Consumption of both fish oil and selenium yeast together had a synergistic effect-The population of Tregs and MDSC decreased as opposed to increase of anti-tumor immunity when both fish oil and selenium were supplemented simultaneously, whereby losses of body weight and muscle/fat mass were alleviated significantly. On the other hand, (-)-Epigallocatechin-3-gallate (EGCG), another potential anti-cachectic nutrient, down-regulates the expressions of NF-kB as well as downstream mediators, ubiquitin ligases, MuRF-1 and MAFbX in skeletal muscle. Chemotherapeutic agent, docetaxel, significantly reduced muscle mass and splenocytes number, and increase serum IL-6 and IL-1 beta levels in normal mice. Surprisingly, within tumor treatment, chemotherapeutic agent, such as docetaxel, cisplatin and 5-FU are capable of inhibiting the number of MDSC and Tregs found in the spleens of tumor-bearing mice with no significant reductions in CD4+ T cells, CD8+ T cells and NK cells. However, chemotherapeutic agent still exhibited side effect on muscle atrophy, which docetaxel treatment showed a significant increase in myostatin and its mediated signaling activates FOXO-1, and leads to proteolysis. In order to diminished chemotherapeutic agent-induced side effect, we using the Chinese herbal complex (Scutellaria baicalensis and Qing-Shu-Yi-Qi-Tang) combined with 5-FU in half of standard dosage to investigate anti-tumor and anti-cachectic activity. As a result, tumor masses and losses of carcass were found to be significantly decreased. This combination otherwise increased both Th1/Th2 ratio and NK cytotoxicity. Thus, the combination of Scutellaria baicalensis and Qing-Shu-Yi-Qi-Tang is able to ameliorate cachectic symptoms and positively stimulate anti-tumor immunity while undergoing chemotherapy. Moreover, treatment of animals with the combined nutritional components (addition of fish oil (fo) or selenium yeast (se)), significantly reduced levels of IL-6, TNF-alpha and myostatin in muscle in tumor-bearing while undergoing chemotherapy, and effectively attenuated the depression of skeletal muscle weight and also inhibited proteolytic relative signaling. Collectively, these findings indicate that nutritional intervention with combined nutritional components (fish oil and selenium yeast) or Chinese herbal complex (Scutellaria baicalensis and Qing-Shu-Yi-Qi-Tang) or EGCG were able to reverse cachectic symptoms, such as reduce muscle loss and to promote anti-tumor immunity dramatically in cancer or combined with chemotherapy, and thus may contributes to the enhancement of clinical outcomes in cancer patients.
誌謝 i
中文摘要 ii
ABSTRACT iv
CONTENTS vi
TABLE OF CONTENTS viii
LIST OF FIGURES ix
ABBREVIATIONS xii
CHAPTER I. Literature Review 1
1.1 Lung cancer 1
1.2 Chemotherapy 1
1.3 Cachexia 3
1.3.1 Impairment of immune functions 3
1.3.2 Skeletal muscle loss 6
1.3.3 Mediators influencing muscle degradation in cachexia 8
1.4 Nutraceutical 12
CHAPTER II. Characterization of cachectic symptoms in lung cancer or combined with chemotherapy 20
2.1 Introduction 20
2.2 Materials and Methods 22
2.3 Results 25
2.4 Discussion 29
CHAPTER III. Reduction of splenic immunosuppressive cells and enhancement of anti-tumor immunity by nutritional supplementation 43
3.1 Introduction 43
3.2 Materials and Methods 46
3.3 Results 51
3.4 Discussion 60
CHAPTER IV. Nutritional intervention attenuates skeletal muscle atrophy in lung cancer cachexia 75
4.1 Introduction 75
4.2 Materials and Methods 77
4.3 Results 81
4.4 Discussion 89
CHAPTER V. Conclusions 106
LITERATURE CITED 110
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