Quercetin、genistein及borage oil單獨或合併使用對cisplatin誘發之肌肉流失的影響

Cisplatin (CDDP) 為臨床上常見用來治療癌症的化療藥物，雖然CDDP有良好抑制癌細胞的能力，但其造成的副作用如造成肌肉流失，卻也限制了其使用劑量。研究顯示quercetin、genistein和γ-次亞麻油酸這三種食物中的機能性成份具有增加化療藥物抑制腫瘤生長之作用，並具有減緩化療藥物不良副作用及癌症惡病質的影響，然而合併使用是否具加乘效應並不清楚，因此本實驗以A549細胞異種移植裸鼠模式，探討單獨及合併使用quercetin、genistein及富含γ-次亞麻油酸之borage oil對CDDP抑制腫瘤及其誘發之不良副作用的影響。雄性裸鼠在皮下注射A549肺癌細胞3週後，隨機分為六組：Control、CDDP、CDDP+Q、CDDP+G、CDDP+QG、CDDP+QGB，CDDP採用腹腔注射 (5mg/kg B.W. 一週一次)；Q和G是飼料中添加0.1% quercetin或genistein；B則是管餵borage oil 150 μl，一週三次。結果顯示，單獨CDDP處理的組別顯著抑制腫瘤生長，單獨或合併使用Q、G、B的組別則不具有加強此抑制效果之作用。單獨CDDP處理的組別顯著降低裸鼠體重、副睪脂肪及腓腸肌重量，單獨或合併使用Q、G、B的組別並不具回復體重及副睪脂肪重量之效果，卻能減緩CDDP誘發之肌肉流失。CDDP處理之裸鼠亦出現前肢抓力下降的現象，單獨使用G或合併使用Q、G、B則具有回復前肢抓力的趨勢。與控制組相比單獨CDDP處理的組別顯著降低裸鼠活動力表現，單獨或合併使用Q、G、B則明顯回復裸鼠活動力表現，進一步檢測肌肉相關蛋白發現，與單獨CDDP處理組別相比，單獨或合併各機能性成分皆能回復myosin heavy chain，並同時減少muscle RING-finger protein-1 及muscle atrophy F-box的蛋白表現量。CDDP合併各項機能性成分皆能降低血漿及腓腸肌中促發炎激素TNF-α、IL-1β及IL-6及增加血漿抗發炎激素IL-10含量。然而，上述效果在單獨及合併使用功能性成分的組別效果相當。綜合上述，我們發現quercetin、genistein及γ-次亞麻油酸具抑制CDDP誘發之肌肉流失的潛力。然而三者合併使用並不具加成效果。

Cisplatin is a widely used chemotherapeutic agent in cancer treatment. However, cisplatin may cause several dose-limiting side-effects such as muscle wasting. Studies show that quercetin, genistein and γ-linolenic acid, three functional compounds in foods, may enhance the anti-tumor effect of chemotherapeutic agent, and may improve body weight or muscle loss caused by cancer or cancer therapy. However, little has been known about the combined effects of these three compounds. In this study, we used a nude mice xenograft model to investigate the individual and combined effects of quercetin, genistein or borage oil (rich in γ-linolenic acid) on tumor growth as well as weight, fat and muscle loss in nude mice treated with cisplatin. Male nude mice were injected A549 cells into the flank. After 4 weeks, the tumor-bearing mice were randomly administrated with the following treatments: CDDP, CDDP+Q, CDDP+G, CDDP+QG and CDDP+QGB (CDDP: cisplatin, 5 mg/kg BW/week; Q: 0.1 % quercetin containing diet; G: 0.1% genistein containing diet; B: 150 μl borage oil, three times a week) for 8 weeks. We first showed that CDDP alone significantly inhibited tumor growth. Q, G, and B alone or in combination did not enhance the anti-tumor effect of CDDP. On the other hand, CDDP significantly induced body, fat and muscle loss. CDDP also decreased the grip strength. Q, G and B alone or combined similarly tended to reduce the gastrocnemius muscle loss and increased the grip strength in tumor-bearing mice treated with CDDP. Furthermore, CDDP also reduced locomotor activity in tumor-bearing mice, while Q, G and B alone or combined significantly restored locomotor activity. In consistent, we found that Q, G, QG and QGB significantly increased myosin heavy chain expression as well as decreased the muscle RING-finger protein-1 and muscle atrophy F-box expression in gastrocnemius muscle compared to the CDDP alone group (p<0.05) . In addition, Q, G, QG and QGB attenuated the levels of proinflammatory cytokines, (TNF-α, IL-1β and IL-6) in the plasma and muscle induced by CDDP and increased the level of IL-10, an anti-inflammatory cytokines, in the plasma (p<0.05) . However, all of the above effects of Q, G, and B alone or in combination were not significantly different. In conclusion, this study demonstrates that Q, G and B alone or in combination reduce cisplatin-induced muscle wasting. However, there are no additive effects for the combined supplements. Further studies are warranted to investigate the possible reasons.