Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia.
Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia.
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SS-31靶向线粒体改善癌症和化疗诱导的恶病质的全身能量状态。
DOI：
10.3390/cancers13040850
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发表时间：
2021-02-18
期刊：
影响因子：
5.2
通讯作者：
Penna F
中科院分区：
文献类型：
--
作者：
Ballarò R;Lopalco P;Audrito V;Beltrà M;Pin F;Angelini R;Costelli P;Corcelli A;Bonetto A;Szeto HH;O'Connell TM;Penna F
癌症恶病质是一种衰弱综合症，由肿瘤生长和化疗引起。骨骼肌是恶病质期间受影响的主要组织之一，表现为代谢和功能改变，导致进行性组织消耗。在目前的研究中，我们旨在通过线粒体靶向化合物SS-31药理学上改善代谢功能来对抗恶病质。用c26携带小鼠分别接受化疗（奥沙利铂+ 5-氟尿嘧啶）或不接受化疗获得实验性癌症恶病质。事实证明，SS-31有效地挽救了一些由肿瘤和化疗引起的骨骼肌和肝脏代谢障碍，改善了全身能量控制。不幸的是，当难治性恶病质出现时，这种效果在疾病晚期不再存在。总的来说，我们提供了针对线粒体功能的潜在新疗法的证据，以抵消或延缓癌症恶病质。目的：恶病质是一种复杂的代谢综合征，常见于癌症患者，并因化疗而加重。在癌症宿主的骨骼肌中，线粒体功能异常导致氧化能力降低和细胞内ATP降低。方法：本研究旨在评估线粒体靶向化合物SS-31在接受化疗（OXFU：奥沙利铂加5-氟尿嘧啶）或未接受化疗的C26小鼠中抵消肌肉萎缩和代谢改变的能力。结果：携带C26 （C26）小鼠线粒体功能障碍与心磷脂脂肪酸链改变有关。SS-31选择性靶向心磷脂部分抵消了机体消耗，阻止了糖酵解肌纤维面积的减少。SS-31促进肌肉线粒体琥珀酸脱氢酶（SDH）活性并挽救细胞内ATP水平，尽管它不能抵消线粒体蛋白质的损失。逐渐增加SS-31给C26 OXFU小鼠的剂量，在难治性终末期疾病（28天）发作之前，对身体和肌肉体重减轻有短暂（21天）的有益影响。第21天，SS-31可防止线粒体丢失和自噬/自噬异常。分析了骨骼肌、肝脏和血浆代谢组，发现肿瘤宿主的能量和蛋白质代谢发生了显著变化。SS-31部分调节了骨骼肌和肝脏代谢组，可能反映了系统能量稳态的改善。结论：研究结果表明，在预防癌症恶病质方面，靶向线粒体功能可能与靶向蛋白质合成代谢/分解代谢同样重要。考虑到这一点，包括SS-31在内的前瞻性多模式治疗是有必要的。
Cancer cachexia is a debilitating syndrome, caused by both tumor growth and chemotherapy. The skeletal muscle is one of the main tissues affected during cachexia, presenting with altered metabolism and function, leading to progressive tissue wasting. In the current study we aimed at counteracting cachexia by pharmacologically improving metabolic function with the mitochondria-targeted compound SS-31. Experimental cancer cachexia was obtained using C26-bearing mice either receiving chemotherapy (oxaliplatin plus 5-fluorouracil) or not. SS-31 proved effective in rescuing some of the metabolic impairments imposed by both tumor and chemotherapy in the skeletal muscle and the liver, improving systemic energy control. Unfortunately, such effects were no longer present at late disease stages when refractory cachexia ensued. Overall, we provide evidence of potential new treatments targeting mitochondrial function in order to counteract or delay cancer cachexia. Objective: Cachexia is a complex metabolic syndrome frequently occurring in cancer patients and exacerbated by chemotherapy. In skeletal muscle of cancer hosts, reduced oxidative capacity and low intracellular ATP resulting from abnormal mitochondrial function were described. Methods: The present study aimed at evaluating the ability of the mitochondria-targeted compound SS-31 to counteract muscle wasting and altered metabolism in C26-bearing (C26) mice either receiving chemotherapy (OXFU: oxaliplatin plus 5-fluorouracil) or not. Results: Mitochondrial dysfunction in C26-bearing (C26) mice associated with alterations of cardiolipin fatty acid chains. Selectively targeting cardiolipin with SS-31 partially counteracted body wasting and prevented the reduction of glycolytic myofiber area. SS-31 prompted muscle mitochondrial succinate dehydrogenase (SDH) activity and rescued intracellular ATP levels, although it was unable to counteract mitochondrial protein loss. Progressively increased dosing of SS-31 to C26 OXFU mice showed transient (21 days) beneficial effects on body and muscle weight loss before the onset of a refractory end-stage condition (28 days). At day 21, SS-31 prevented mitochondrial loss and abnormal autophagy/mitophagy. Skeletal muscle, liver and plasma metabolomes were analyzed, showing marked energy and protein metabolism alterations in tumor hosts. SS-31 partially modulated skeletal muscle and liver metabolome, likely reflecting an improved systemic energy homeostasis. Conclusions: The results suggest that targeting mitochondrial function may be as important as targeting protein anabolism/catabolism for the prevention of cancer cachexia. With this in mind, prospective multi-modal therapies including SS-31 are warranted.
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影响因子：
2.9
作者：
Niels T;Tomanek A;Freitag N;Schumann M
通讯作者：
Schumann M
DOI：
10.1002/jcsm.12232
发表时间：
2017-12
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Brown JL;Rosa-Caldwell ME;Lee DE;Blackwell TA;Brown LA;Perry RA;Haynie WS;Hardee JP;Carson JA;Wiggs MP;Washington TA;Greene NP
通讯作者：
Greene NP
影响因子：
5.3
作者：
den Kamp, C. M. Op;Langen, R. C.;Schols, A. M.
通讯作者：
Schols, A. M.
影响因子：
25.7
作者：
Dumas, Jean-Francois;Goupille, Caroline;Couet, Charles
通讯作者：
Couet, Charles
影响因子：
4.8
作者：
Mitchell, Wayne;Ng, Emily A.;Alder, Nathan N.
通讯作者：
Alder, Nathan N.