Development of a traditional Chinese medicine-based agent for the treatment of cancer cachexia

doi:10.1002/jcsm.13028

	Development of a traditional Chinese medicine-based agent for the treatment of cancer cachexia
	Wu, Kun-Chang 10,11; Chu, Po-Chen 12,13; Cheng, Yu-Jung 14,15,16; Li, Chia-Ing 17,18; Tian, Jingkui 4,19; Wu, Hsing-Yu 1; Wu, Szu-Hsien 2,10; Lai, Yi-Chun 11; Kao, Hsiang-Han 3; Hsu, Ao-Lin 5,9,11
刊名	JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE
	2022-06-19
关键词	Cachexia Traditional Chinese medicine Muscle atrophy C-26 tumour-bearing model Caenorhabditis elegans model
ISSN号	2190-5991
DOI	10.1002/jcsm.13028
通讯作者	Lin, Hsiang-Wen(hsiangwl@gmail.com) ; Lin, Chih-Hsueh(d5496@mail.cmuh.org.tw)
英文摘要	Background Despite recent advances in understanding the pathophysiology of cancer cachexia, prevention/treatment of this debilitating disease remains an unmet medical need. Methods We developed an integrated, multi-tiered strategy involving both in vitro and in vivo muscle atrophy platforms to identify traditional Chinese medicine (TCM)-based anti-cachectic agents. In the initial screening, we used inflammatory cytokine-induced atrophy of C2C12 myotubes as a phenotypic screening platform to assess the protective effects of TCMs. The selected TCMs were then evaluated for their abilities to protect Caenorhabditis elegans from age-related reduction of mobility and contractility, followed by the C-26 colon adenocarcinoma mouse model of cachexia to confirm the anti-muscle atrophy effects (body/skeletal muscle weights, fibre size distribution, grip strengths, and serum IL-6). Transcriptome analysis, quantitative real-time polymerase chain reaction, and immunoblotting were performed to gain understanding of the potential mechanism(s) by which effective TCM protected against C26 tumour-induced muscle atrophy. Results Of 29 widely used TCMs, Dioscorea radix (DR) and Mu Dan Pi (MDP) showed a complete protection (all P values, 0.0002) vis-a-vis C26 conditioned medium control in the myotube atrophy platform. MDP exhibited a unique ability to ameliorate age-associated decreases in worm mobility, accompanied by improved total body contractions, relative to control (P < 0.0001 and <0.01, respectively), which, however, was not noted with DR. This differential in vivo protective effect between MDP and DR was also confirmed in the C-26 mouse model. MDP at 1000 mg/kg (MDP-H) was effective in protecting body weight loss (P < 0.05) in C-26 tumour-bearing mice without changing food or water intake, accompanied by the restoration of the fibre size distribution of hindleg skeletal muscles (P < 0.0001) and the forelimb grip strength (P < 0.05). MDP-treated C-26-tumour-bearing mice were alert, showed normal posture and better body conditions, and exhibited lower serum IL-6 levels (P = 0.06) relative to vehicle control. This decreased serum IL-6 was associated with the in vitro suppressive effect of MDP (25 and 50 mu g/mL) on IL-6 secretion into culture medium by C26 cells. RNA-seq analysis, followed by quantitative real-time polymerase chain reaction and/or immunoblotting, shows that MDP's anti-cachectic effect was attributable to its ability to reverse the C-26 tumour-induced re-programming of muscle homoeostasis-associated gene expression, including that of two cachexia drivers (MuRF1 and Atrogin-1), in skeletal muscles. Conclusion All these findings suggest the translational potential of MDP to foster new strategies for the prevention and/or treatment of cachexia. The protective effect of MDP on other types of muscle atrophy such as sarcopenia might warrant investigations.
资助项目	China Medical University (CMU)[CMU108-Z-7] ; China Medical University (CMU)[CMU109-Z-07] ; China Medical University (CMU)[CMU110-Z-07] ; China Medical University Hospital[DMR-110-080] ; Ministry of Science and Technology[MOST 109-2622-8-039-001-TB1] ; Ministry of Science and Technology[MOST 110-2622-8-039-004-TB1] ; Drug Development Center, China Medical University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE), in Taiwan
WOS关键词	CC-CHEMOKINE ; C. ELEGANS ; IN-VITRO ; MODEL
WOS研究方向	Geriatrics & Gerontology ; General & Internal Medicine
语种	英语
出版者	WILEY
WOS记录号	WOS:000812726200001
资助机构	China Medical University (CMU) ; China Medical University Hospital ; Ministry of Science and Technology ; Drug Development Center, China Medical University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE), in Taiwan
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/131283]
专题	中国科学院合肥物质科学研究院
通讯作者	Lin, Hsiang-Wen; Lin, Chih-Hsueh
作者单位	1.Acad Sinica, Inst Biol Chem, Taipei, Taiwan 2.China Med Univ, Inst New Drug Dev, Taichung, Taiwan 3.China Med Univ Hosp, Dept Family Med, Taichung, Taiwan 4.Zhejiang Univ, Coll Biomed Engn & Instrument Sci, Hangzhou, Peoples R China 5.China Med Univ, PhD Program Aging, Taichung, Taiwan 6.China Med Univ Hosp, Dept Geriatr Med, Taichung, Taiwan 7.Univ Illinois, Coll Pharm, Dept Pharm Syst Outcomes & Policy, Chicago, IL 60612 USA 8.China Med Univ Hosp, Dept Pharm, Taichung, Taiwan 9.Univ Michigan, Sch Med, Dept Internal Med, Div Geriatr & Palliat Med, Ann Arbor, MI USA 10.China Med Univ, Sch Pharm, Coll Pharm, Taichung, Taiwan
推荐引用方式 GB/T 7714	Wu, Kun-Chang,Chu, Po-Chen,Cheng, Yu-Jung,et al. Development of a traditional Chinese medicine-based agent for the treatment of cancer cachexia[J]. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE,2022.
APA	Wu, Kun-Chang.,Chu, Po-Chen.,Cheng, Yu-Jung.,Li, Chia-Ing.,Tian, Jingkui.,...&Lin, Chih-Hsueh.(2022).Development of a traditional Chinese medicine-based agent for the treatment of cancer cachexia.JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE.
MLA	Wu, Kun-Chang,et al."Development of a traditional Chinese medicine-based agent for the treatment of cancer cachexia".JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE (2022).