Quercetin及eicosapentaenoic acid單獨或合併使用對cisplatin誘發之脂肪流失的影響

Individual or combined effects of quercetin and eicosapentaenoic acid on cisplatin-induced fat loss

黃怡紋(Yi-Wen Huang)

指導教授 ： 葉姝蘭

中山醫學大學/健康管理學院/營養學系碩士班/碩士(2017年)

摘要

順鉑 (cis-diamminedichloroplatinum II, cisplatin; CDDP) 為常見應用於癌症的化療藥物，然而CDDP可能引起許多副作用，包括肌肉和脂肪組織的減少。研究指出槲皮素 (quercetin, Q；一種類黃酮) 和二十碳五烯酸 (eicosapentaenoic acid, EPA；一種ω-3的多元不飽和脂肪酸) 皆可能增加化療藥物的抗腫瘤效果，並且減少藥物的有害影響，但合併使用效果如何並不清楚，因此本研究利用異種移植小鼠模式，探討Q和EPA單獨或合併對CDDP腫瘤生長、體重、肌肉與脂肪重量以及肝腎毒性的影響。雄性裸鼠皮下注射A549肺癌細胞，4週後分成七組，分別為：control組、CDDP組 (單獨以腹腔注射給予CDDP 2 mg/kg B.W.；一週一次) 、CDDP+EPA組 (CDDP處理合併管餵EPA 125 mg/kg B.W.；一周三次) 、CDDP+IQ (CDDP處理合併以腹腔注射給予Q 10 mg/kg B.W.；一周三次) 、CDDP+OQ (CDDP處理合併1 % Q飼料) 、CDDP+EPA+IQ組及CDDP+EPA+OQ組，處理8週後犧牲，進行各項分析。結果顯示，EPA、IQ或OQ個別增強CDDP的抗腫瘤性的效果IQ, EPA> OQ，EPA和IQ單獨給予顯著降低CDDP誘發的裸鼠體重及副睪脂肪重量流失，此外，EPA、IQ或OQ降低CDDP誘發的肝腎毒性，不過與我們預期不同的是，EPA+IQ或EPA+OQ的合併效果對上述參數的影響效果並未較單獨作用好。我們進一步發現，CDDP增加腫瘤組織中p53及p21蛋白表現，IQ和OQ單獨會增強CDDP此一作用，但EPA卻有消減作用。另方面我們發現EPA、IQ和OQ單獨或合併補充皆能降低血漿、腫瘤、脂肪和肌肉組織中CDDP誘發的促發炎激素及脂質過氧化產物 (thiobarbituric acid reactive substances, TBARs) ，EPA和IQ單獨或合併亦增加脂肪組織中fatty acid synthase (FAS，一種參與脂肪生成之酵素) 但降低carnitine palmitoyl transferase 1 (CPT1，一種參與脂肪分解之酵素) 的蛋白質表現量；而OQ卻同時增加此二者表現量。綜合以上，我們的結果顯示 EPA、IQ或OQ有增加CDDP抗癌效果，並可抑制CDDP誘發的體重及脂肪流失及肝腎毒性的趨勢，但EPA跟IQ或OQ在這些參數上的影響效果，並未達相加，在一些檢測項目甚至有些拮抗的情形，這與他們對p53、p21、FAS 及CPT1有不一致的調節可能有關。

關鍵字

順鉑 ； 槲皮素 ； 二十碳五烯酸 ； 脂肪酸合成酶肉鹼棕梠醯基轉移酶p53 ； p21 ； 脂肪組織

並列摘要

cis-diamminedichloroplatinum II (CDDP) is a common chemotherapy for various cancers. However, CDDP may induce many harmful effects including the loss of muscle and adipose tissue. Several studies show that both quercetin (Q; a flavonoid) and eicosapentaenoic acid (EPA; a ω-3 polyunsaturated fatty acid) alone increase the antitumor effects of chemotherapeutic agents and reduce the deleterious effects of these therapies. However, little has been known about the combined effect of these two compounds. Therefore, in this study, we used a tumor-bearing mice model to investigate the individual or combined effect of Q and EPA on the effects of CDDP on the growth of tumor, the weight of body, gastrocnemius muscle and epididymal fat, as well as the toxicities in kidney and liver. Male nude mice were injected with A549 cells into the flank. After 4 weeks, the tumor-bearing mice were randomly treated with cisplatin (2 mg/kg, once a week; CDDP) alone, or in combination with EPA (125 mg/kg, 3 times a weeks; EPA), Q or both for 8 weeks. Q was given by intraperitoneal injection (10 mg/kg, 3 times a weeks; IQ), or a Q containing diet (1% quercetin diet; OQ). The result showed that EPA, IQ or OQ enhanced the anti-tumor effect of CDDP in the order IQ, EPA>OQ. EPA and IQ alone also significantly reduced the weight loss of body and epididymal fat induced by CDDP. In addition, EPA, IQ and OQ reduced CDDP-induced toxicities in kidney and liver. However the combined effects of EPA+IQ or EPA+OQ were not better than the individual effects in all these parameters. Furthermore, we found that CDDP increased the expression of p53 and p21. IQ and OQ enhanced such effects of CDDP, while EPA decreased the effect of CDDP. EPA, IQ and OQ alone or in combination attenuated the levels of proinflammatory cytokines and lipid peroxidation products (thiobarbituric acid reactive substances, TBARs) induced by CDDP in plasma, tumor or muscle and fat tissues. EPA and IQ alone or in combination increased fatty acid synthase (FAS, an enzyme involved in fatty acid synthesis) but decreased carnitine palmitoyl transferase 1 (CTP1, an enzyme involved in beta-oxidation of fatty acids) protein expression in the fat tissues, while OQ increased both FAS and CPT1 expression. In conclusion, the present study demonstrates EPA, IQ and OQ tend to enhance the anti-cancer effect of CDDP and decrease CDDP-induced body and epididymal fat weight loss as well as the toxicities in kidney and liver in tumor-bearing mice. However, the combined effects of EPA and IQ or OQ are not additive but seem antagonistic in some parameters. This may be associated with the different effects of EPA, IQ and OQ on the expression of p53, p21, FAS and CPT1.

並列關鍵字

cisplatin ； quercetin ； eicosapentaenoic acid ； fatty acid synthase ； carnitine palmitoyl transferase 1 ； p53 ； p21 ； adipose tissue

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