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Association between cancer metabolism and muscle atrophy

암 대사와 근위축의 연관성

  • Yeonju, Seo (Department of Food Science and Biotechnology, Kyungpook National University) ;
  • Ju-Ock, Nam (Department of Food Science and Biotechnology, Kyungpook National University)
  • Received : 2022.11.03
  • Accepted : 2022.12.01
  • Published : 2022.12.31

Abstract

Skeletal muscle accounts for about 40-50% of body weight and is an important tissue that performs various functions, such as maintaining posture, supporting soft tissues, maintaining body temperature, and respiration. Cancer, which occurs widely around the world, causes cancer cachexia accompanied by muscular atrophy, which reduces the effectiveness of anticancer drugs and greatly reduces the quality of life and survival rate of cancer patients. Therefore, research to improve cancer cachexia is ongoing. However, there are few studies on the link between cancer and muscle atrophy. Cancer cells exhibit distinct microenvironment and metabolism from tumor cells, including tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), and insulin resistance due to the Warburg effect. Therefore, we summarize the microenvironment and metabolic characteristics of cancer cells, and the molecular mechanisms of muscle atrophy that can be affected by cytokine and insulin resistance. In addition, this suggests the possibility of improving cancer cachexia of substances affecting TAM, TAN, and Warburg effect. We also summarize the mechanisms identified so far through single agents and the signaling pathways mediated by them that may ameliorate cancer cachexia.

골격근은 체중의 약 40-50%를 차지하며 자세 유지, 연조직 지지, 체온 유지, 호흡 등 다양한 기능을 수행하는 중요한 조직이다. 전 세계적으로 광범위하게 발생하는 암은 근위축을 동반한 암 악액질을 일으켜 항암제의 효과를 떨어뜨리고 암환자의 삶의 질과 생존율을 크게 떨어뜨린다. 따라서 암 악액질을 개선하기 위한 연구가 진행 중이지만 암과 근육 위축 사이의 연관성에 관한 연구는 거의 없다. 암 세포는 종양 관련 대식세포(TAM), 종양 관련 호중구(TAN) 및 Warburg 효과로 인한 인슐린 저항성을 포함하여 독특한 미세 환경 및 대사를 나타낸다. 따라서 암세포의 미세환경과 대사적 특성, 사이토카인과 인슐린 저항성에 의해 영향을 받을 수 있는 근육 위축의 분자적 기전을 정리하였다. 또한 이는 TAM, TAN, Warburg 효과에 영향을 미치는 물질의 암 악액질 개선 가능성을 시사한다. 본 논문에서는 또한 암 악액질을 개선할 수 있는 단일 화합물 및 이들에 의해 매개되는 신호 전달 경로를 통해 지금까지 확인된 메커니즘을 정리하였다.

Keywords

References

  1. Argiles JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Manas L (2016) Skeletal muscle regulates metabolism via interorgan crosstalk: roles in health and disease. J Am Med Dir Assoc 17: 789-796  https://doi.org/10.1016/j.jamda.2016.04.019
  2. Schutz Y (2011) Protein Turnover, Ureagenesis and Gluconeogenesis. Int J Vitam Nutr Res 81: 101-107. doi: 10.1024/0300-9831/a000064 
  3. Conte E, Bresciani E, Rizzi L, Cappellari O, De Luca A, Torsello A, Liantonio A (2020) Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies. Int J Mol Sci 21: 10.3390/ijms21041242 
  4. Guigni BA, Callahan DM, Tourville TW, Miller MS, Fiske B, Voigt T, Korwin-Mihavics B, Anathy V, Dittus K, Toth MJ (2018) Skeletal muscle atrophy and dysfunction in breast cancer patients: role for chemotherapy-derived oxidant stress. Am J Physio-Cell Physiol 315: C744-C756. doi: 10.1152/ajpcell.00002.2018 
  5. Hiensch AE, Bolam KA, Mijwel S, Jeneson JAL, Huitema ADR, Kranenburg O, van der Wall E, Rundqvist H, Wengstrom Y, May AM (2020) Doxorubicin-induced skeletal muscle atrophy: Elucidating the underlying molecular pathways. Acta Physiol (Oxf) 229: e13400. doi: 10.1111/apha.13400 
  6. Costamagna D, Duelen R, Penna F, Neumann D, Costelli P, Sampaolesi M (2020) Interleukin-4 administration improves muscle function, adult myogenesis, and lifespan of colon carcinoma-bearing mice. J Cachexia Sarcopenia Muscle 11: 783-801. doi: 10.1002/jcsm.12539 
  7. Yuan L, Han J, Meng Q, Xi Q, Zhuang Q, Jiang Y, Han Y, Zhang B, Fang J, Wu G (2015) Muscle-specific E3 ubiquitin ligases are involved in muscle atrophy of cancer cachexia: An in vitro and in vivo study. Oncol Rep 33: 2261-2268. doi: 10.3892/or.2015.3845 
  8. Fernandez GJ, Ferreira JH, Vechetti Jr IJ, De Moraes LN, Cury SS, Freire PP, Gutierrez J, Ferretti R, Dal-Pai-Silva M, Rogatto SR (2020) MicroRNA-mRNA co-sequencing identifies transcriptional and post-transcriptional regulatory networks underlying muscle wasting in cancer cachexia. Front Genet 11: 541. doi: 10.3389/fgene.2020.00541 
  9. Zhang W, Sun W, Gu X, Miao C, Feng L, Shen Q, Liu X, Zhang X (2022) GDF-15 in tumor-derived exosomes promotes muscle atrophy via Bcl-2/caspase-3 pathway. Cell Death Discovery 8: 162. doi: 10.1038/s41420-022-00972-z 
  10. Wang F, Liu H, Hu L, Liu Y, Duan Y, Cui R, Tian W (2018) The Warburg effect in human pancreatic cancer cells triggers cachexia in athymic mice carrying the cancer cells. BMC Cancer 18: 360. doi: 10.1186/s12885-018-4271-3 
  11. Stewart GD, Skipworth RJ, Fearon KC (2006) Cancer cachexia and fatigue. Clin Med (Lond) 6: 140-143. doi: 10.7861/clinmedicine.6-2-140 
  12. Petruzzelli M, Wagner EF (2016) Mechanisms of metabolic dysfunction in cancer-associated cachexia. Genes Dev 30: 489-501. doi: 10.1101/gad.276733.115 
  13. Vuorinen-Markkola H, Koivisto VA, Yki-Jarvinen H (1992) Mechanisms of Hyperglycemia-Induced Insulin Resistance in Whole Body and Skeletal Muscle of Type I Diabetic Patients. Diabetes 41: 571-580. doi: 10.2337/diab.41.5.571 
  14. Wang X, Hu Z, Hu J, Du J, Mitch WE (2006) Insulin Resistance Accelerates Muscle Protein Degradation: Activation of the Ubiquitin-Proteasome Pathway by Defects in Muscle Cell Signaling. Endocrinology 147: 4160-4168. doi: 10.1210/en.2006-0251 
  15. Coleman ME, DeMayo F, Yin KC, Lee HM, Geske R, Montgomery C, Schwartz RJ (1995) Myogenic Vector Expression of Insulin-like Growth Factor I Stimulates Muscle Cell Differentiation and Myofiber Hypertrophy in Transgenic Mice. J Biol Chem 270: 12109-12116. doi: 10.1074/jbc.270.20.12109 
  16. Behring JB, van der Post S, Mooradian AD, Egan MJ, Zimmerman MI, Clements JL, Bowman GR, Held JM (2020) Spatial and temporal alterations in protein structure by EGF regulate cryptic cysteine oxidation. Science Signaling 13: eaay7315. doi: 10.1126/scisignal.aay7315 
  17. Kvandova M, Dovinova I (2017) Functioning of the PPAR Gamma and its Effect on Cardiovascular and Metabolic Diseases. Metabolic Syndrome: 1-41 
  18. Huot JR, Marino JS, Turner MJ, Arthur ST (2020) Notch Inhibition via GSI Treatment Elevates Protein Synthesis in C2C12 Myotubes. Biology 9. doi: 10.3390/biology9060115 
  19. Yu M, Wang H, Xu Y, Yu D, Li D, Liu X, Du W (2015) Insulin-like growth factor-1 (IGF-1) promotes myoblast proliferation and skeletal muscle growth of embryonic chickens via the PI3K/Akt signalling pathway. Cell Biol Int 39: 910-922. doi: 10.1002/cbin.10466 
  20. Fruman D, Limon J (2012) Akt and mTOR in B Cell Activation and Differentiation. Front Immunol 3: 10.3389/fimmu.2012.00228 
  21. Pallafacchina G, Calabria E, Serrano AL, Kalhovde JM, Schiaffino S (2002) A protein kinase B-dependent and rapamycin-sensitive pathway controls skeletal muscle growth but not fiber type specification. Proc Natl Acad Sci 99: 9213-9218. doi: 10.1073/pnas.142166599 
  22. Shu L, Zhang X, Houghton PJ (2002) Myogenic Differentiation Is Dependent on Both the Kinase Function and the N-terminal Sequence of Mammalian Target of Rapamycin. J Biol Chem 277: 16726-16732. doi: 10.1074/jbc.M112285200 
  23. Busby S, Ebright RH (1999) Transcription activation by catabolite activator protein (CAP). J Mol Biol 293: 199-213. doi: 10.1006/jmbi.1999.3161 
  24. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM (2009) Active-Site Inhibitors of mTOR Target RapamycinResistant Outputs of mTORC1 and mTORC2. PLOS Biology 7: e1000038. doi: 10.1371/journal.pbio.1000038 
  25. Lai Y-C, Liu Y, Jacobs R, Rider Mark H (2012) A novel PKB/Akt inhibitor, MK-2206, effectively inhibits insulin-stimulated glucose metabolism and protein synthesis in isolated rat skeletal muscle. Biochem J 447: 137-147. doi: 10.1042/BJ20120772 
  26. Bauer DE, Hatzivassiliou G, Zhao F, Andreadis C, Thompson CB (2005) ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24: 6314-6322. doi: 10.1038/sj.onc.1208773 
  27. Paradies G, Paradies V, Ruggiero FM, Petrosillo G (2019) Role of Cardiolipin in Mitochondrial Function and Dynamics in Health and Disease: Molecular and Pharmacological Aspects. Cells 8. doi: 10.3390/cells8070728 
  28. Das S, Morvan F, Morozzi G, Jourde B, Minetti GC, Kahle P, Rivet H, Brebbia P, Toussaint G, Glass DJ, Fornaro M (2017) ATP Citrate Lyase Regulates Myofiber Differentiation and Increases Regeneration by Altering Histone Acetylation. Cell Reports 21: 3003-3011. doi: 10.1016/j.celrep.2017.11.038 
  29. Chen Y, Song Y, Du W, Gong L, Chang H, Zou Z (2019) Tumor-associated macrophages: an accomplice in solid tumor progression. J Biomed Sci 26: 78. doi: 10.1186/s12929-019-0568-z 
  30. Erreni M, Mantovani A, Allavena P (2011) Tumor-associated Macrophages (TAM) and Inflammation in Colorectal Cancer. Cancer Microenviron 4: 141-154. doi: 10.1007/s12307-010-0052-5 
  31. Ruffell B, Coussens Lisa M (2015) Macrophages and Therapeutic Resistance in Cancer. Cancer Cell 27: 462-472. doi: 10.1016/j.ccell.2015.02.015 
  32. Lin L, Chen Y-S, Yao Y-D, Chen J-Q, Chen J-N, Huang S-Y, Zeng Y-J, Yao H-R, Zeng S-H, Fu Y-S, Song E-W (2015) CCL18 from tumor-associated macrophages promotes angiogenesis in breast cancer. Oncotarget Vol 6, No 33: 34758-34773. doi: 10.18632/oncotarget.5325 
  33. Steitz AM, Steffes A, Finkernagel F, Unger A, Sommerfeld L, Jansen JM, Wagner U, Graumann J, Muller R, Reinartz S (2020) Tumor-associated macrophages promote ovarian cancer cell migration by secreting transforming growth factor beta induced (TGFBI) and tenascin C. Cell Death Dis 11: 249. doi: 10.1038/s41419-020-2438-8 
  34. Zeng X-Y, Xie H, Yuan J, Jiang X-Y, Yong J-H, Zeng D, Dou Y-Y, Xiao S-S (2019) M2-like tumor-associated macrophages-secreted EGF promotes epithelial ovarian cancer metastasis via activating EGFR-ERK signaling and suppressing lncRNA LIMT expression. Cancer Biol Ther 20: 956-966. doi: 10.1080/15384047.2018.1564567 
  35. Liu L, Wang X, Li X, Wu X, Tang M, Wang X (2018) Upregulation of IGF1 by tumor-associated macrophages promotes the proliferation and migration of epithelial ovarian cancer cells. Oncol Rep 39: 818-826. doi: 10.3892/or.2017.6148 
  36. Chen Y, Zhang S, Wang Q, Zhang X (2017) Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein. JHematol Oncol 10: 36. doi: 10.1186/s13045-017-0408-0 
  37. Masucci MT, Minopoli M, Carriero MV (2019) Tumor Associated Neutrophils. Their Role in Tumorigenesis, Metastasis, Prognosis and Therapy. Front Oncol 9: 10.3389/fonc.2019.01146 
  38. Hajizadeh F, Aghebati Maleki L, Alexander M, Mikhailova MV, Masjedi A, Ahmadpour M, Hashemi V, Jadidi-Niaragh F (2021) Tumor-associated neutrophils as new players in immunosuppressive process of the tumor microenvironment in breast cancer. Life Sci 264: 118699. doi: 10.1016/j.lfs.2020.118699 
  39. Koga Y, Matsuzaki A, Suminoe A, Hattori H, Hara T (2004) Neutrophil-Derived TNF-Related Apoptosis-Inducing Ligand (TRAIL): A Novel Mechanism of Antitumor Effect by Neutrophils. Cancer Res 64: 1037-1043. doi: 10.1158/0008-5472.CAN-03-1808 
  40. Ludwig AT, Moore JM, Luo Y, Chen X, Saltsgaver NA, O'Donnell MA, Griffith TS (2004) Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand: A Novel Mechanism for Bacillus Calmette-Guerin-Induced Antitumor Activity. Cancer Res 64: 3386-3390. doi: 10.1158/0008-5472.Can-04-0374 
  41. Kayagaki N, Yamaguchi N, Nakayama M, Takeda K, Akiba H, Tsutsui H, Okamura H, Nakanishi K, Okumura K, Yagita H (1999) Expression and function of TNF-related apoptosis-inducing ligand on murine activated NK cells. J Immunol 163: 1906-1913  https://doi.org/10.4049/jimmunol.163.4.1906
  42. Szulc-Kielbik I, Klink M (2022) Polymorphonuclear Neutrophils and Tumors: Friend or Foe? Exp Suppl 113: 141-167. doi: 10.1007/978-3-7091-1300-4_7 
  43. Chetram MA, Bethea DA, Odero-Marah VA, Don-Salu-Hewage AS, Jones KJ, Hinton CV (2013) ROS-mediated activation of AKT induces apoptosis via pVHL in prostate cancer cells. Mol Cell Biochem 376: 63-71. doi: 10.1007/s11010-012-1549-7 
  44. Kwak A-W, Lee M-J, Lee M-H, Yoon G, Cho S-S, Chae J-I, Shim J-H (2021) The 3-deoxysappanchalcone induces ROS-mediated apoptosis and cell cycle arrest via JNK/p38 MAPKs signaling pathway in human esophageal cancer cells. Phytomedicine 86: 153564. doi: 10.1016/j.phymed.2021.153564 
  45. Tazzyman S, Lewis CE, Murdoch C (2009) Neutrophils: key mediators of tumour angiogenesis. Int J Exp Pathol 90: 222-231. doi: 10.1111/j.1365-2613.2009.00641.x 
  46. McCourt M, Wang JH, Sookhai S, Redmond HP (1999) Proinflammatory Mediators Stimulate Neutrophil-Directed Angiogenesis. Arch Surg 134: 1325-1331. doi: 10.1001/archsurg.134.12.1325 
  47. Huang S, Van Arsdall M, Tedjarati S, McCarty M, Wu W, Langley R, Fidler IJ (2002) Contributions of Stromal Metalloproteinase-9 to Angiogenesis and Growth of Human Ovarian Carcinoma in Mice. JNCI: J Natl Cancer Inst 94: 1134-1142. doi: 10.1093/jnci/94.15.1134 
  48. Coussens LM, Tinkle CL, Hanahan D, Werb Z (2000) MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103: 481-490  https://doi.org/10.1016/S0092-8674(00)00139-2
  49. Zugmaier G, Paik S, Wilding G, Knabbe C, Bano M, Lupu R, Deschauer B, Simpson S, Dickson RB, Lippman M (1991) Transforming growth factor beta 1 induces cachexia and systemic fibrosis without an antitumor effect in nude mice. Cancer Res 51: 3590-3594 
  50. Allen RE, Boxhorn LK (1987) Inhibition of skeletal muscle satellite cell differentiation by transforming growth factor-beta. J Cell Physiol 133: 567-572. doi: 10.1002/jcp.1041330319 
  51. Li Y, Foster W, Deasy BM, Chan Y, Prisk V, Tang Y, Cummins J, Huard J (2004) Transforming Growth Factor-β1 Induces the Differentiation of Myogenic Cells into Fibrotic Cells in Injured Skeletal Muscle: A Key Event in Muscle Fibrogenesis. Am J Pathol 164: 1007-1019. doi: 10.1016/S0002-9440(10)63188-4 
  52. Abrigo J, Campos F, Simon F, Riedel C, Cabrera D, Vilos C, Cabello-Verrugio C (2018) TGF-β requires the activation of canonical and non-canonical signalling pathways to induce skeletal muscle atrophy. Biol Chem 399: 253-264. doi: doi: 10.1515/hsz-2017-0217 
  53. Janssen SPM, Gayan-Ramirez G, Van Den Bergh A, Herijgers P, Maes K, Verbeken E, Decramer M (2005) Interleukin-6 Causes Myocardial Failure and Skeletal Muscle Atrophy in Rats. Circulation 111: 996-1005. doi: 10.1161/01.CIR.0000156469.96135.0D 
  54. Fujita J, Tsujinaka T, Yano M, Ebisui C, Saito H, Katsume A, Akamatsu K, Ohsugi Y, Shiozaki H, Monden M (1996) Anti-interleukin-6 receptor antibody prevents muscle atrophy in colon-26 adenocarcinoma-bearing mice with modulation of lysosomal and ATP-ubiquitin-dependent proteolytic pathways. Int J Cancer 68: 637-643. doi: 10.1002/(sici)1097-0215(19961127)68:5<637::Aid-ijc14>3.0.Co;2-z 
  55. Hu W, Ru Z, Zhou Y, Xiao W, Sun R, Zhang S, Gao Y, Li X, Zhang X, Yang H (2019) Lung cancer-derived extracellular vesicles induced myotube atrophy and adipocyte lipolysis via the extracellular IL-6-mediated STAT3 pathway. Biochimica et Biophysica Acta (BBA) - Mol Cell Biol Lipids 1864: 1091-1102. doi: 10.1016/j.bbalip.2019.04.006 
  56. Soda K, Kawakami M, Kashii A, Miyata M (1995) Manifestations of cancer cachexia induced by colon 26 adenocarcinoma are not fully ascribable to interleukin-6. Int J Cancer 62: 332-336. doi: 10.1002/ijc.2910620317 
  57. Kurosaka M, Machida S (2013) Interleukin-6-induced satellite cell proliferation is regulated by induction of the JAK2/STAT3 signalling pathway through cyclin D1 targeting. Cell Prolif 46: 365-373. doi: 10.1111/cpr.12045 
  58. Lu S, Li Y, Shen Q, Zhang W, Gu X, Ma M, Li Y, Zhang L, Liu X, Zhang X (2021) Carnosol and its analogues attenuate muscle atrophy and fat lipolysis induced by cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle 12: 779-795. doi: 10.1002/jcsm.12710 
  59. Dun Y-l, Zhou X-l, Guan H-s, Yu G-l, Li C-x, Hu T, Zhao X, Cheng X-l, He X-x, Hao J-j (2015) Low molecular weight guluronate prevents TNF-α-induced oxidative damage and mitochondrial dysfunction in C2C12 skeletal muscle cells. Food Funct 6: 3056-3064. doi: 10.1039/C5FO00533G 
  60. Li W, Moylan JS, Chambers MA, Smith J, Reid MB (2009) Interleukin-1 stimulates catabolism in C2C12 myotubes. Am J Physiol Cell Physiol 297: C706-C714. doi: 10.1152/ajpcell.00626.2008 
  61. Cohen TV, Many GM, Fleming BD, Gnocchi VF, Ghimbovschi S, Mosser DM, Hoffman EP, Partridge TA (2015) Upregulated IL-1β in dysferlin-deficient muscle attenuates regeneration by blunting the response to pro-inflammatory macrophages. Skeletal Muscle 5: 24. doi: 10.1186/s13395-015-0048-4 
  62. Li H, Mittal A, Makonchuk DY, Bhatnagar S, Kumar A (2009) Matrix metalloproteinase-9 inhibition ameliorates pathogenesis and improves skeletal muscle regeneration in muscular dystrophy. Hum Mol Genet 18: 2584-2598. doi: 10.1093/hmg/ddp191 
  63. Arsic N, Zacchigna S, Zentilin L, Ramirez-Correa G, Pattarini L, Salvi A, Sinagra G, Giacca M (2004) Vascular endothelial growth factor stimulates skeletal muscle regeneration in Vivo. Mol Ther 10: 844-854. doi: 10.1016/j.ymthe.2004.08.007 
  64. Karvinen H, Pasanen E, Rissanen TT, Korpisalo P, Vahakangas E, Jazwa A, Giacca M, Yla-Herttuala S (2011) Long-term VEGF-A expression promotes aberrant angiogenesis and fibrosis in skeletal muscle. Gene Ther 18: 1166-1172. doi: 10.1038/gt.2011.66 
  65. Deng B, Wehling-Henricks M, Villalta SA, Wang Y, Tidball JG (2012) IL-10 Triggers Changes in Macrophage Phenotype That Promote Muscle Growth and Regeneration. J Immunol 189: 3669. doi: 10.4049/jimmunol.1103180 
  66. Callaway CS, Delitto AE, D'Lugos AC, Patel R, Nosacka RL, Delitto D, Deyhle MR, Trevino JG, Judge SM, Judge AR (2019) IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy. Cancers 11. doi: 10.3390/cancers11121863 
  67. Santiloni Cury S, de Moraes D, Paccielli Freire P, de Oliveira G, Venancio Pereira Marques D, Javier Fernandez G, Dal-Pai-Silva M, Nishida Hasimoto E, Pintor dos Reis P, Regina Rogatto S, Francisco Carvalho R (2019) Tumor Transcriptome Reveals High Expression of IL-8 in Non-Small Cell Lung Cancer Patients with Low Pectoralis Muscle Area and Reduced Survival. Cancers 11. doi: 10.3390/cancers11091251 
  68. Cheng H, Huang H, Guo Z, Chang Y, Li Z (2021) Role of prostaglandin E2 in tissue repair and regeneration. Theranostics 11: 8836-8854. doi: 10.7150/thno.63396 
  69. Abrigo J, Rivera JC, Simon F, Cabrera D, Cabello-Verrugio C (2016) Transforming growth factor type beta (TGF-β) requires reactive oxygen species to induce skeletal muscle atrophy. Cellular Signalling 28: 366-376. doi: 10.1016/j.cellsig.2016.01.010 
  70. Abrigo J, Simon F, Cabrera D, Cordova G, Trollet C, Cabello-Verrugio C (2018) Central role of transforming growth factor type beta 1 in skeletal muscle dysfunctions: an update on therapeutic strategies. Curr Protein Pept Sci 19: 1189-1200. doi: 10.2174/1389203718666171117101916 
  71. Shen Q, Kuang J-X, Miao C-X, Zhang W-L, Li Y-W, Zhang X-W, Liu X (2022) Alantolactone ameliorates cancer cachexia-associated muscle atrophy mainly by inhibiting the STAT3 signaling pathway. Phytomedicine 95: 153858. doi: 10.1016/j.phymed.2021.153858 
  72. Patel HJ, Patel BM (2017) TNF-α and cancer cachexia: Molecular insights and clinical implications. Life Sciences 170: 56-63. doi: 10.1016/j.lfs.2016.11.033 
  73. Luo G, Hershko DD, Robb BW, Wray CJ, Hasselgren P-O (2003) IL-1β stimulates IL-6 production in cultured skeletal muscle cells through activation of MAP kinase signaling pathway and NF-κB. Am J Physiol Regul Integr Comp Physiol 284: R1249-R1254. doi: 10.1152/ajpregu.00490.2002 
  74. Sadeghi M, Keshavarz-Fathi M, Baracos V, Arends J, Mahmoudi M, Rezaei N (2018) Cancer cachexia: Diagnosis, assessment, and treatment. Crit Rev Oncol Hematol 127: 91-104. doi: 10.1016/j.critrevonc.2018.05.006 
  75. Aoyagi T, Terracina KP, Raza A, Matsubara H, Takabe K (2015) Cancer cachexia, mechanism and treatment. World J Gastrointest Oncol 7: 17-29. doi: 10.4251/wjgo.v7.i4.17 
  76. Hamburger AW, Parnes H, Gordon GB, Shantz LM, O'Donnell KA, Aisner J (1988) Megestrol acetate-induced differentiation of 3T3-L1 adipocytes in vitro. Semin Oncol 15: 76-78 
  77. Castle S, Nguyen C, Joaquin A, Coyne B, Heuston C, Chan A, Percy L, Ohmen J (1995) Megesterol acetate suspension therapy in the treatment of geriatric anorexia/cachexia in nursing home patients. J Am Geriatr Soc 43: 835-836. doi: 10.1111/j.1532-5415.1995.tb07065.x 
  78. Park S (2010) Ghrelin. Endocrinol Metab 25: 258-263. doi: 10.3803/EnM.2010.25.4.258 
  79. Dixit VD, Schaffer EM, Pyle RS, Collins GD, Sakthivel SK, Palaniappan R, Lillard JW, Jr., Taub DD (2004) Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Investig 114: 57-66. doi: 10.1172/JCI21134 
  80. Miao C, Lv Y, Zhang W, Chai X, Feng L, Fang Y, Liu X, Zhang X (2017) Pyrrolidine Dithiocarbamate (PDTC) Attenuates Cancer Cachexia by Affecting Muscle Atrophy and Fat Lipolysis. Front Pharmacol 8: 10.3389/fphar.2017.00915 
  81. Shukla SK, Dasgupta A, Mehla K, Gunda V, Vernucci E, Souchek J, Goode G, King R, Mishra A, Rai I, Nagarajan S, Chaika NV, Yu F, Singh PK (2015) Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth. Oncotarget Vol 6, No 38: 41146-41161. doi: 10.18632/oncotarget.5843 
  82. Sun R, Zhang S, Hu W, Lu X, Lou N, Yang Z, Chen S, Zhang X, Yang H (2016) Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPβ-regulated atrogin1 expression in cancer cachexia. Am J Physiol Cell Physiol 311: C101-C115. doi: 10.1152/ajpcell.00344.2015 
  83. Wang H, Lai Y-J, Chan Y-L, Li T-L, Wu C-J (2011) Epigallocatechin-3-gallate effectively attenuates skeletal muscle atrophy caused by cancer cachexia. Cancer Letters 305: 40-49. doi: 10.1016/j.canlet.2011.02.023 
  84. Jung YY, Ko J-H, Um J-Y, Sethi G, Ahn KS (2021) A Novel Role of Bergamottin in Attenuating Cancer Associated Cachexia by Diverse Molecular Mechanisms. Cancers 13. doi: 10.3390/cancers13061347 
  85. Chun J, Li R-J, Cheng M-S, Kim YS (2015) Alantolactone selectively suppresses STAT3 activation and exhibits potent anticancer activity in MDA-MB-231 cells. Cancer Lett 357: 393-403. doi: 10.1016/j.canlet.2014.11.049 
  86. Zheng H, Yang L, Kang Y, Chen M, Lin S, Xiang Y, Li C, Dai X, Huang X, Liang G, Zhao C (2019) Alantolactone sensitizes human pancreatic cancer cells to EGFR inhibitors through the inhibition of STAT3 signaling. Mol Carcinog 58: 565-576. doi: 10.1002/mc.22951 
  87. Ahmad B, Gamallat Y, Su P, Husain A, Rehman AU, Zaky MY, Bakheet AMH, Tahir N, Xin Y, Liang W (2021) Alantolactone induces apoptosis in THP-1 cells through STAT3, survivin inhibition, and intrinsic apoptosis pathway. Chem Biol Drug Des 97: 266-272. doi: 10.1111/cbdd.13778 
  88. Chen L, Yang Q, Zhang H, Wan L, Xin B, Cao Y, Zhang J, Guo C (2020) Cryptotanshinone prevents muscle wasting in CT26-induced cancer cachexia through inhibiting STAT3 signaling pathway. J Ethnopharmacol 260: 113066. doi: 10.1016/j.jep.2020.113066 
  89. Lu S, Zhang Y, Li H, Zhang J, Ci Y, Han M (2020) Ginsenoside Rb1 can ameliorate the key inflammatory cytokines TNF-α and IL-6 in a cancer cachexia mouse model. BMC Complementary Medicine and Therapies 20: 11. doi: 10.1186/s12906-019-2797-9