Supportive Care in Cancer

, Volume 24, Issue 3, pp 1189–1198 | Cite as

Reversal of muscle atrophy by Zhimu and Huangbai herb pair via activation of IGF-1/Akt and autophagy signal in cancer cachexia

  • Pengwei Zhuang
  • Jinbao Zhang
  • Yan Wang
  • Mixia Zhang
  • Lili Song
  • Zhiqiang Lu
  • Lu Zhang
  • Fengqi Zhang
  • Jing Wang
  • Yanjun Zhang
  • Hongjun Wei
  • Hongyan Li
Original Article



Muscle atrophy is the prominent clinical feature of cancer-induced cachexia. Zhimu and Huangbai herb pair (ZBHP) has been used since ancient China times and have been phytochemically investigated for constituents that might cause anti-cancer, diabetes, and their complication. In this study, the effects and mechanisms of ZBHP on reversal of muscle atrophy were explored.


C57BL/6 mice implanted with colon-26 adenocarcinoma were chosen to develop cancer cachexia for evaluating the effects of ZBHP on reversal of muscle atrophy. The body weight, survival time, inflammatory cytokines, and pathological changes of muscle were monitored. In addition, IGF-1/Akt and autophagy pathway members were analyzed to interpret the mechanism of drug response.


The function and morphology of skeletal muscle in cachexia model were significantly disturbed, and the survival time was shortened. Consistently, inflammatory cytokines and muscle atrophy-related atrogin-1, MuRF1, and FOXO3 were significantly increased, and IGF-1/Akt and autophagy signal pathways were depressed. Treatment with ZBHP significantly alleviated tumor-free body weight reduction and cachexia-induced changes in cytokines and prolonged survival. ZBHP treatment not only inhibited the muscle atrophy-related genes but also activated the IGF-1/Akt and autophagy signal pathways to facilitate the protein synthesis.


The results revealed that ZBHP treatment could inhibit the muscle atrophy induced by cancer cachexia and prolong the survival time, and ZBHP may be of value as a pharmacological alternative in treatment of cancer cachexia.


Cancer cachexia Skeletal muscle atrophy Zhimu and Huangbai herb pair Autophagy IGF-1/Akt 



This work was supported by the National Natural Science Foundation of China (no. 81403213) and Program for Changjiang Scholars and Innovative Research Team in University (“PCSIRT”, IRT 14R41).

Conflict of interest

We do not have any financial relationship with the organization that sponsored the research and the authorship. Besides, we have full control of all primary data, and we agreed to allow the journal to have the data if requested by the reviewer.


  1. 1.
    Adams V, Mangner N, Gasch A, Krohne C, Gielen S, Hirner S, Thierse HJ, Witt CC, Linke A, Schuler G, Labeit S (2008) Induction of MuRF1 is essential for TNF-alpha-induced loss of muscle function in mice. J Mol Biol 384:48–59CrossRefPubMedGoogle Scholar
  2. 2.
    Argiles JM, Lopez-Soriano FJ (1999) The role of cytokines in cancer cachexia. Med Res Rev 19:223–248CrossRefPubMedGoogle Scholar
  3. 3.
    Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294:1704–1708CrossRefPubMedGoogle Scholar
  4. 4.
    Broussard SR, McCusker RH, Novakofski JE, Strle K, Shen WH, Johnson RW, Freund GG, Dantzer R, Kelley KW (2003) Cytokine-hormone interactions: tumor necrosis factor alpha impairs biologic activity and downstream activation signals of the insulin-like growth factor I receptor in myoblasts. Endocrinology 144:2988–2996CrossRefPubMedGoogle Scholar
  5. 5.
    Carson JA, Baltgalvis KA (2010) Interleukin 6 as a key regulator of muscle mass during cachexia. Exerc Sport Sci Rev 38:168–176PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Chambon C, Duteil D, Vignaud A, Ferry A, Messaddeq N, Malivindi R, Kato S, Chambon P, Metzger D (2010) Myocytic androgen receptor controls the strength but not the mass of limb muscles. Proc Natl Acad Sci U S A 107:14327–14332PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Clavel S, Siffroi-Fernandez S, Coldefy AS, Boulukos K, Pisani DF, Derijard B (2010) Regulation of the intracellular localization of Foxo3a by stress-activated protein kinase signaling pathways in skeletal muscle cells. Mol Cell Biol 30:470–480PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Costelli P, Carbo N, Tessitore L, Bagby GJ, Lopez-Soriano FJ, Argiles JM, Baccino FM (1993) Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model. J Clin Invest 92:2783–2789PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Costelli P, Muscaritoli M, Bossola M, Penna F, Reffo P, Bonetto A, Busquets S, Bonelli G, Lopez-Soriano FJ, Doglietto GB, Argiles JM, Baccino FM, Rossi Fanelli F (2006) IGF-1 is downregulated in experimental cancer cachexia. Am J Physiol Regul, Integr Comp Physiol 291:R674–R683CrossRefGoogle Scholar
  10. 10.
    Diogo CV, Machado NG, Barbosa IA, Serafim TL, Burgeiro A, Oliveira PJ (2011) Berberine as a promising safe anti-cancer agent - is there a role for mitochondria? Curr Drug Targets 12:850–859CrossRefPubMedGoogle Scholar
  11. 11.
    Fearon KC (2008) Cancer cachexia: developing multimodal therapy for a multidimensional problem. Eur J Cancer 44:1124–1132CrossRefPubMedGoogle Scholar
  12. 12.
    Frost RA, Nystrom GJ, Jefferson LS, Lang CH (2007) Hormone, cytokine, and nutritional regulation of sepsis-induced increases in atrogin-1 and MuRF1 in skeletal muscle. Am J Physiol Endocrinol Metab 292:E501–E512CrossRefPubMedGoogle Scholar
  13. 13.
    Glass DJ (2005) Skeletal muscle hypertrophy and atrophy signaling pathways. Int J Biochem Cell Biol 37:1974–1984CrossRefPubMedGoogle Scholar
  14. 14.
    Grumati P, Coletto L, Sabatelli P, Cescon M, Angelin A, Bertaggia E, Blaauw B, Urciuolo A, Tiepolo T, Merlini L, Maraldi NM, Bernardi P, Sandri M, Bonaldo P (2010) Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat Med 16:1313–1320CrossRefPubMedGoogle Scholar
  15. 15.
    Iizuka N, Hazama S, Yoshimura K, Yoshino S, Tangoku A, Miyamoto K, Okita K, Oka M (2002) Anticachectic effects of the natural herb Coptidis rhizoma and berberine on mice bearing colon 26/clone 20 adenocarcinoma. Int J Cancer 99:286–291CrossRefPubMedGoogle Scholar
  16. 16.
    Latres E, Amini AR, Amini AA, Griffiths J, Martin FJ, Wei Y, Lin HC, Yancopoulos GD, Glass DJ (2005) Insulin-like growth factor-1 (IGF-1) inversely regulates atrophy-induced genes via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. J Biol Chem 280:2737–2744CrossRefPubMedGoogle Scholar
  17. 17.
    Ma C, Fan M, Tang Y, Li Z, Sun Z, Ye G, Huang C (2008) Identification of major alkaloids and steroidal saponins in rat serum by HPLC-diode array detection-MS/MS following oral administration of Huangbai-Zhimu herb-pair Extract. Biomed Chromatogr 22:835–850CrossRefPubMedGoogle Scholar
  18. 18.
    Mammucari C, Schiaffino S, Sandri M (2008) Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle. Autophagy 4:524–526CrossRefPubMedGoogle Scholar
  19. 19.
    Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, Metzger D, Reggiani C, Schiaffino S, Sandri M (2009) Autophagy is required to maintain muscle mass. Cell Metab 10:507–515CrossRefPubMedGoogle Scholar
  20. 20.
    Masiero E, Sandri M (2010) Autophagy inhibition induces atrophy and myopathy in adult skeletal muscles. Autophagy 6:307–309CrossRefPubMedGoogle Scholar
  21. 21.
    Pandey SN, Cabotage J, Shi R, Dixit M, Sutherland M, Liu J, Muger S, Harper SQ, Nagaraju K, Chen YW (2012) Conditional over-expression of PITX1 causes skeletal muscle dystrophy in mice. Biol Open 1:629–639PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Sandri M (2010) Autophagy in skeletal muscle. FEBS Lett 584:1411–1416CrossRefPubMedGoogle Scholar
  23. 23.
    Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL (2004) Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117:399–412PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Schmidt K, von Haehling S, Doehner W, Palus S, Anker SD, Springer J, Schmidt K, von Haehling S, Doehner W, Palus S, Anker SD, Springer J (2011) IGF-1 treatment reduces weight loss and improves outcome in a rat model of cancer cachexia. J Cachex Sarcopenia Muscle 2:105–109CrossRefGoogle Scholar
  25. 25.
    Schulze PC, Gielen S, Adams V, Linke A, Mobius-Winkler S, Erbs S, Kratzsch J, Hambrecht R, Schuler G (2003) Muscular levels of proinflammatory cytokines correlate with a reduced expression of insulinlike growth factor-I in chronic heart failure. Basic Res Cardiol 98:267–274PubMedGoogle Scholar
  26. 26.
    Simons JP, Schols AM, Buurman WA, Wouters EF (1999) Weight loss and low body cell mass in males with lung cancer: relationship with systemic inflammation, acute-phase response, resting energy expenditure, and catabolic and anabolic hormones. Clin Sci 97:215–223CrossRefPubMedGoogle Scholar
  27. 27.
    Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ (2004) The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 14:395–403CrossRefPubMedGoogle Scholar
  28. 28.
    Strassmann G, Fong M, Kenney JS, Jacob CO (1992) Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 89:1681–1684PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Tanaka Y, Eda H, Tanaka T, Udagawa T, Ishikawa T, Horii I, Ishitsuka H, Kataoka T, Taguchi T (1990) Experimental cancer cachexia induced by transplantable colon 26 adenocarcinoma in mice. Cancer Res 50:2290–2295PubMedGoogle Scholar
  30. 30.
    Tang YH, Sun ZL, Fan MS, Li ZX, Huang CG (2012) Anti-diabetic effects of TongGuanWan, a Chinese traditional herbal formula, in C57BL/KsJ-db/db mice. Planta Med 78:18–23CrossRefPubMedGoogle Scholar
  31. 31.
    Tisdale MJ (1997) Biology of cachexia. J Natl Cancer Inst 89:1763–1773CrossRefPubMedGoogle Scholar
  32. 32.
    Tolkovsky AM (2010) Autophagy thwarts muscle disease. Nat Med 16:1188–1190CrossRefPubMedGoogle Scholar
  33. 33.
    Wang N, Feng Y, Zhu M, Siu FM, Ng KM, Che CM (2013) A novel mechanism of XIAP degradation induced by timosaponin AIII in hepatocellular carcinoma. Biochim Biophys Acta 1833:2890–2899CrossRefPubMedGoogle Scholar
  34. 34.
    Zaki MH, Nemeth JA, Trikha M (2004) CNTO 328, a monoclonal antibody to IL-6, inhibits human tumor-induced cachexia in nude mice. Int J Cancer 111:592–595CrossRefPubMedGoogle Scholar
  35. 35.
    Zhang J, Zhuang P, Wang Y, Song L, Zhang M, Lu Z, Zhang L, Wang J, Alemu PN, Zhang Y, Wei H, Li H (2014) Reversal of muscle atrophy by Zhimu-Huangbai herb-pair via Akt/mTOR/FoxO3 signal pathway in streptozotocin-induced diabetic mice. PLoS One 9:e100918PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Zhou X, Wang JL, Lu J, Song Y, Kwak KS, Jiao Q, Rosenfeld R, Chen Q, Boone T, Simonet WS, Lacey DL, Goldberg AL, Han HQ (2010) Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142:531–543CrossRefPubMedGoogle Scholar
  37. 37.
    Zhuang P, Zhang Y, Cui G, Bian Y, Zhang M, Zhang J, Liu Y, Yang X, Isaiah AO, Lin Y, Jiang Y (2012) Direct stimulation of adult neural stem/progenitor cells in vitro and neurogenesis in vivo by salvianolic acid B. PLoS One 7:e35636PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Zhuang PW, Cui GZ, Zhang YJ, Zhang MX, Guo H, Zhang JB, Lu ZQ, Isaiah AO, Lin YX (2013) Baicalin regulates neuronal fate decision in neural stem/progenitor cells and stimulates hippocampal neurogenesis in adult rats. CNS Neurosci Ther 19:154–162CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Pengwei Zhuang
    • 1
    • 2
    • 3
  • Jinbao Zhang
    • 1
    • 4
  • Yan Wang
    • 1
    • 2
  • Mixia Zhang
    • 1
    • 2
  • Lili Song
    • 1
    • 2
  • Zhiqiang Lu
    • 1
  • Lu Zhang
    • 1
  • Fengqi Zhang
    • 1
  • Jing Wang
    • 1
  • Yanjun Zhang
    • 1
    • 2
  • Hongjun Wei
    • 3
  • Hongyan Li
    • 3
  1. 1.Chinese Materia Medica CollegeTianjin University of Traditional Chinese MedicineTianjinChina
  2. 2.Tianjin State Key Laboratory of Modern Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
  3. 3.Tianjin JF-Pharmaland Technology Development Co., LtdTianjinChina
  4. 4.Gansu University of Chinese MedicineLanzhouChina

Personalised recommendations