| Abstract: | 瑪卡(Lepidium meyenii)為南美洲一種十字花科植物，具抗發炎、抗氧化、抗高血壓和保護肝臟等保健作用。結直腸癌是常見的惡性腫瘤之一，化療藥物FOLFIRI (5-Fluorouracil、Leucovorin與Irinotecan)雖可有效抑制結直腸癌細胞生長，但研究也發現FOLFIRI會造成骨骼肌耗損副作用。惡病質常出現於晚期惡性腫瘤患者中，惡病質的骨骼肌肉嚴重耗竭，不僅導致體重減輕，且會影響患者的生活品質、降低生存率和對化療的耐受性。證據顯示癌細胞分泌的促蛋白質異化物質及促發炎細胞激素，激活泛素-蛋白酶體途徑(ubiquitin-proteasome pathway, UPP)和自噬-溶酶體途徑(autophagy-lysosome pathway, ALP)，促進骨骼肌肉蛋白質異化作用，是癌症患者發生骨骼肌消耗的重要因素。本研究以BALB/c小鼠皮下接種CT-26結直腸癌細胞及腹腔注射化學治療藥物FOLFIRI (2次/週)的研究模式評估灌食瑪卡水萃物(30 mg/mice，3次/週)對改善FOLFIRI化學治療藥物引起腫瘤小鼠的骨骼肌耗損與腸道細胞凋亡等副作用的功效。與攜帶CT-26結腸直腸癌的小鼠相比，給予FOLFIRI化學治療藥物的腫瘤小鼠體重和腓腸肌、股四頭肌、比目魚肌和伸趾長肌重量顯著降低，且骨骼肌肉束橫切面積也顯著縮小，而瑪卡的補充顯著改善了腫瘤小鼠的體重減輕與骨骼肌肉流失。此外，補充瑪卡顯著減少FOLFIRI誘導腫瘤小鼠腓腸肌Myosin heavy chain (MyHC)蛋白質表現下降以及UPP相關因子Atrogin-1和MuRF1和ALP相關因子LC3 II和Beclin-1和Caspase-3的增加。與使用FOLFIRI治療的腫瘤小鼠相比，補充瑪卡顯著降低了比目魚肌中中IL-6、IL-1β、和tumor necrosis factor alpha (TNF-α)濃度，值得注意的是，補充瑪卡也顯著降低了FOLFIRI治療的腫瘤小鼠腓腸肌中Mitogen-activated protein kinases (MAPKs)的磷酸化以及細胞核中CCAAT/Enhancer binding protein δ (C/EBP-δ)、Nuclear factor-kappa B p65 (NF-κB p65)和Forkhead transcription factors 1 (FoxO1)與肌肉蛋白質分解相關轉錄因子表現。補充瑪卡水萃物亦提高細胞核nuclear factor erythroid 2與抗氧化酵素glutathione reductase、catalase、heme oxygenase-1、superoxide dismutase1、superoxide dismutase2及NAD(P)H quinone oxidoreductase 1蛋白質表現。另外發現，給予FOLFIRI治療顯著增加空腸Cleaved PARP和Caspase-3蛋白質表現，瑪卡可改善上述與細胞凋亡相關蛋白質表現。綜合以上可知，補充瑪卡可改善FOLFIRI對腫瘤小鼠惡病質肌肉耗損症狀，此與減少骨骼肌中UPP、ALP路徑活化、發炎反應及降低MAPKs、C/EBP-δ和NF-κB信號傳導的活化，增加抗氧化能力有關。未來研究需進一步探討對於改善腫瘤小鼠給予化學治療藥物誘導的惡病質，補充瑪卡之最有效劑量。
Maca (Lepidium meyenii), a cruciferous plant in South America, has anti-inflammatory, anti-oxidant, anti-hypertensive and hepato-protective effect. Colorectal cancer is one of the common malignant tumors. The chemotherapy compounds, FOLFIRI (5-fluorouracil, leucovorin, and irinotecan), can effectively inhibit the growth of colorectal cancer cells, but the study found that FOLFIRI treatment caused skeletal muscle wasting side effect.Cachexia often occurs in patients with advanced malignant tumors characterized weight loss and severe skeletal muscle depletion which decreases patients'' life quality, survival rate and tolerance to chemotherapy treatment. Pro-inflammatory cytokines produced by cancer cells are associated with the activation of ubiquitin- proteasome pathway (UPP) and the autophagy-lysosome pathway (ALP), promotion in skeletal muscle wasting in cancer patients. In order to assay the effect of Maca on cancer cachexia induced muscle wasting, BALB/c mice were injected with CT-26 colorectal cancer cells and then treated with FOLFIRI (twice per week) and oral supplementation with Maca water extract (30 mg per mice) three times a week. Compared with the CT-26 colorectal cancer tumor bearing mice, the body weight as well as the weight of gastrocnemius, quadriceps, soleus muscle and the cross-sectional area of skeletal muscle in tumor bearing mice with FOLFIRI treatment were significantly reduced. Supplementation of Maca significantly improved weight loss and skeletal muscle loss in tumor bearing mice with FOLFIRI treatment. Moreover, the Maca supplementation significantly lessen FOLFIRI induced a decrease in Myosin heavy Chain (MyHC) as well as increases in UPP-related factors muscle atrophy F-box 1 (Atrogin-1) and muscle RING finger protein 1 (MuRF1) and ALP-related factors microtubule-associated protein 1B light chain 3 (LC3) and Beclin-1 as well as Caspase-3 in the gastrocnemius of tumor bearing mice. Compared with tumor bearing mice with FOLFIRI treatment, Maca supplementation significantly reduced IL-6, IL-1β and tumor necrosis factor alpha (TNF-α) mRNA levels in the soleus muscle, Maca supplementation also significantly diminished phosphorylation of Mitogen-activated protein kinases (MAPKs) as well as nuclear protein expression of CCAAT/Enhancer binding protein δ (C/EBP-δ), Nuclear factor-kappa B p65 (NF-κB p65) and Forkhead transcription factors 1 (FoxO1) in gastrocnemius of tumor bearing mice with FOLFIRI treatment. Maca water extract supplementation also significantly improved of nuclear factor nuclear factor erythroid 2 nuclear protein and antioxidant enzymes glutathione reductase, catalase, heme oxygenase-1, superoxide dismutase1, superoxide dismutase2 and NAD(P)H quinone oxidoreductase 1 proteins expression. FOLFIRI treatment significantly increased expression of apoptosis related protein such as Cleaved PARP and Caspase-3 in the jejunal of tumor bearing mice, and Maca supplementation decreased the apoptosis effect of FOLFIRI. In summary, Maca supplementation lessened the effects of FOLFIRI on skeletal muscle wasting through decreases in UPP and ALP pathway as well as inflammatory response accompanied by reducing MAPKs, C/EBP-δ, and NF-κB signal transduction and increasing antioxidant capacity in turor bearing mice. Future research needs explore the most effective dose of Maca supplementation for prevetion of chemotherapy induced cachexia in tumor bearing mice. |
