Abstract
Introduction
Chemotherapy is a major etiology of cachexia. Ginseng products are known to have various anti-cachectic and health-promoting effects, such as inhibiting inflammation and promoting energy production. In particular, BST204, purified ginseng dry extract, contains multiple ginsenosides that can reduce chemotherapy-related fatigue and toxicity.
Objectives
To investigate the effects of BST204 on the alleviation of chemotherapy-induced cachexia using a multimodal approach.
Methods
In a CT26 mouse syngeneic colon cancer model, cachexia was predominantly induced by chemotherapy with 5-fluorouracil (5-FU) than by tumor growth. BST204 at a dose of 100 or 200 mg/kg was administered to 5-FU-treated mice.
Results
BST204 significantly mitigated the decrease in tumor-excluded body weight (change in 5-FU group and BST204 groups: − 13% vs. − 6% on day 7; − 30% vs. − 20% on day 11), muscle volume (− 19% vs. − 11%), and fat volume (− 91% vs. − 56%). The anti-cachectic effect of BST204 was histologically demonstrated by an improved balance between muscle regeneration and degeneration and a decrease in muscle cross-sectional area reduction.
Conclusion
Chemotherapy-induced cachexia was biochemically and metabolically characterized by activated inflammation, enhanced oxidative stress, increased protein degradation, decreased protein stabilization, reduced glucose-mediated energy production, and deactivated glucose-mediated biosynthesis. These adverse effects were significantly improved by BST204 treatment. Overall, our multimodal study demonstrated that BST204 could effectively alleviate chemotherapy-induced cachexia.
Similar content being viewed by others
References
Allu, P. K., Marada, A., Boggula, Y., Karri, S., Krishnamoorthy, T., & Sepuri, N. B. (2015). Methionine sulfoxide reductase 2 reversibly regulates Mge1, a cochaperone of mitochondrial Hsp70, during oxidative stress. Molecular Biology of the Cell, 26, 406–419.
Aoyagi, T., Terracina, K. P., Raza, A., Matsubara, H., & Takabe, K. (2015). Cancer cachexia, mechanism and treatment. World Journal of Gastrointestinal Oncology, 7, 17–29.
Aquila, G., Re Cecconi, A. D., Brault, J. J., Corli, O., & Piccirillo, R. (2020). Nutraceuticals and exercise against muscle wasting during cancer cachexia. Cells, 9(12), 2536.
Ballarò, R., Penna, F., Pin, F., Gómez-Cabrera, M. C., Viña, J., & Costelli, P. (2019). Moderate exercise improves experimental cancer cachexia by modulating the redox homeostasis. Cancers (Basel), 11(3), 285.
Barreto, R., Mandili, G., Witzmann, F. A., Novelli, F., Zimmers, T. A., & Bonetto, A. (2016). Cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. Frontiers in Physiology, 7, 472.
Barreto, R., Waning, D. L., Gao, H., Liu, Y., Zimmers, T. A., & Bonetto, A. (2016). Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs. Oncotarget, 7, 43442–43460.
Benson, A. B., 3rd., Venook, A. P., Cederquist, L., Chan, E., Chen, Y. J., Cooper, H. S., Deming, D., Engstrom, P. F., Enzinger, P. C., Fichera, A., Grem, J. L., Grothey, A., Hochster, H. S., Hoffe, S., Hunt, S., Kamel, A., Kirilcuk, N., Krishnamurthi, S., Messersmith, W. A., & Freedman-Cass, D. (2017). Colon cancer, version 1.2017, NCCN clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network, 15, 370–398.
Bonetto, A., Aydogdu, T., Jin, X., Zhang, Z., Zhan, R., Puzis, L., Koniaris, L. G., & Zimmers, T. A. (2012). JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia. American journal of physiology, 303, E410–E421.
Branco, A., Yoshikawa, F. S. Y., Pietrobon, A. J., & Sato, M. N. (2018). Role of histamine in modulating the immune response and inflammation. Mediators of Inflammation, 2018, 9524075.
Braun, T. P., Szumowski, M., Levasseur, P. R., Grossberg, A. J., Zhu, X., Agarwal, A., & Marks, D. L. (2014). Muscle atrophy in response to cytotoxic chemotherapy is dependent on intact glucocorticoid signaling in skeletal muscle. PLoS ONE, 9, e106489.
Le Bricon, T., Gugins, S., Cynober, L., & Baracos, V. E. (1995). Negative impact of cancer chemotherapy on protein metabolism in healthy and tumor-bearing rats. Metabolism, 44, 1340–1348.
Eskiler, G. G., Bezdegumeli, E., Ozman, Z., Ozkan, A. D., Bilir, C., Kucukakca, B. N., Ince, M. N., Men, A. Y., Aktas, O., Horoz, Y. E., Akpinar, D., Genc, I., & Kaleli, S. (2019). IL-6 mediated JAK/STAT3 signaling pathway in cancer patients with cachexia. Bratislavske Lekarske Listy, 66, 819–826.
Fu, W., Xu, H., Yu, X., Lyu, C., Tian, Y., Guo, M., Sun, J., & Sui, D.J.R.a. . (2018). 20 (S)-Ginsenoside Rg2 attenuates myocardial ischemia/reperfusion injury by reducing oxidative stress and inflammation: Role of SIRT1. RSC Advances, 8(42), 23947–23962.
Hofseth, L. J., & Wargovich, M. J. (2007). Inflammation, Cancer, and Targets of Ginseng. The Journal of Nutrition, 137, 183S-185S.
Jourdain, M., Melly, S., Summermatter, S., & Hatakeyama, S. (2018). Mouse models of cancer-induced cachexia: Hind limb muscle mass and evoked force as readouts. Biochemical and Biophysical Research Communications, 503, 2415–2420.
Kumar Srivastava, A., Khare, P., Kumar Nagar, H., Raghuwanshi, N., & Srivastava, R. (2016). Hydroxyproline: A potential biochemical marker and its role in the pathogenesis of different diseases. Current Protein & Peptide Science, 17, 596–602.
Le Lay, S., Simard, G., Martinez, M. C., & Andriantsitohaina, R. (2014). Oxidative stress and metabolic pathologies: from an adipocentric point of view. Oxidative Medicine and Cellular Longevity, 2014, 908539.
Lee, S. M. (2014). Anti-inflammatory effects of ginsenosides Rg5, Rz1, and Rk1: Inhibition of TNF-alpha-induced NF-kappaB, COX-2, and iNOS transcriptional expression. Phytotherapy Research, 28, 1893–1896.
Li, W., Yan, M. H., Liu, Y., Liu, Z., Wang, Z., Chen, C., Zhang, J., & Sun, Y. S. (2016). Ginsenoside Rg5 Ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of inflammation, oxidative stress, and apoptosis. Nutrients, 8(9), 566.
Lin, X. Y., & Chen, S. Z. (2017). Calpain inhibitors ameliorate muscle wasting in a cachectic mouse model bearing CT26 colorectal adenocarcinoma. Oncology Reports, 37, 1601–1610.
Luo, L., & Liu, M. (2016). Adipose tissue in control of metabolism. Journal of Endocrinology, 231, R77-r99.
Musarò, A. (2014). The basis of muscle regeneration. Advances in Biology, 2014, 612471.
Niu, M., Song, S., Su, Z., Wei, L., Li, L., Pu, W., Zhao, C., Ding, Y., Cao, W., Gao, Q., & Wang, H. (2021). Inhibition of HSP90 reversed STAT3 mediated muscle wasting induced by cancer cachexia. Biorxiv. https://doi.org/10.1101/2021.01.27.428420
Parasuraman, S., Raveendran, R., & Kesavan, R. (2010). Blood sample collection in small laboratory animals. Journal of Pharmacology and Pharmacotherapeutics, 1, 87–93.
Park, H. J., Shim, H. S., Kim, J. Y., Kim, J. Y., Park, S. K., & Shim, I. (2015). Ginseng purified dry extract, bst204, improved cancer chemotherapy-related fatigue and toxicity in mice. Evidence Based Complementary and Alternative Medicine, 2015, 197459.
Park, M. W., Ha, J., & Chung, S. H. (2008). 20(S)-ginsenoside Rg3 enhances glucose-stimulated insulin secretion and activates AMPK. Biological &/and Pharmaceutical Bulletin, 31, 748–751.
Pin, F., Barreto, R., Couch, M. E., Bonetto, A., & O’Connell, T. M. (2019). Cachexia induced by cancer and chemotherapy yield distinct perturbations to energy metabolism. Journal of Cachexia Sarcopenia and Muscle, 10, 140–154.
Pritt, M. L., Hall, D. G., Recknor, J., Credille, K. M., Brown, D. D., Yumibe, N. P., Schultze, A. E., & Watson, D. E. (2008). Fabp3 as a biomarker of skeletal muscle toxicity in the rat: Comparison with conventional biomarkers. Toxicological Sciences, 103, 382–396.
Qi, F., Zheng, Z., Yan, Q., Liu, J., Chen, Y., & Zhang, G. (2018). Comparisons of efficacy, safety, and cost of chemotherapy regimens FOLFOX4 and FOLFIRINOX in rectal cancer: A randomized, multicenter study. Medical Science Monitor, 24, 1970–1979.
Quan-Jun, Y., Yan, H., Yong-Long, H., Li-Li, W., Jie, L., Jin-Lu, H., Jin, L., Peng-Guo, C., Run, G., & Cheng, G. (2017). Selumetinib attenuates skeletal muscle wasting in murine cachexia model through ERK inhibition and AKT activation. Molecular Cancer Therapeutics, 16, 334–343.
Radaelli, G., Piccirillo, A., Birolo, M., Bertotto, D., Gratta, F., Ballarin, C., Vascellari, M., Xiccato, G., & Trocino, A. (2017). Effect of age on the occurrence of muscle fiber degeneration associated with myopathies in broiler chickens submitted to feed restriction. Poultry Science, 96, 309–319.
Rittig, N., Bach, E., Thomsen, H. H., Pedersen, S. B., Nielsen, T. S., Jørgensen, J. O., Jessen, N., & Møller, N. (2016). Regulation of lipolysis and adipose tissue signaling during acute endotoxin-induced inflammation: A human randomized crossover trial. PLoS ONE, 11, e0162167–e0162167.
Schiaffino, S., Dyar, K. A., Ciciliot, S., Blaauw, B., & Sandri, M. (2013). Mechanisms regulating skeletal muscle growth and atrophy. FEBS Journal, 280, 4294–4314.
Seo, J. Y., Lee, J. H., Kim, N. W., Her, E., Chang, S. H., Ko, N. Y., Yoo, Y. H., Kim, J. W., Seo, D. W., Han, J. W., Kim, Y. M., & Choi, W. S. (2005a). Effect of a fermented ginseng extract, BST204, on the expression of cyclooxygenase-2 in murine macrophages. International Immunopharmacology, 5, 929–936.
Seo, J. Y., Lee, J. H., Kim, N. W., Kim, Y. J., Chang, S. H., Ko, N. Y., Her, E., Yoo, Y. H., Kim, J. W., Lee, B. Y., Lee, H. Y., Kim, Y. M., & Choi, W. S. (2005b). Inhibitory effects of a fermented ginseng extract, BST204, on the expression of inducible nitric oxide synthase and nitric oxide production in lipopolysaccharide-activated murine macrophages. Journal of Pharmacy and Pharmacology, 57, 911–918.
Shen, L., Haas, M., Wang, D. Q. H., May, A., Lo, C. C., Obici, S., Tso, P., Woods, S. C., & Liu, M. (2015). Ginsenoside Rb1 increases insulin sensitivity by activating AMP-activated protein kinase in male rats. Physiological Reports, 3, e12543.
da Silva, C. G., Jarzyna, R., Specht, A., & Kaczmarek, E. (2006). Extracellular nucleotides and adenosine independently activate AMP-activated protein kinase in endothelial cells: involvement of P2 receptors and adenosine transporters. Circulation Research, 98, e39-47.
Stewart, M. D., Lopez, S., Nagandla, H., Soibam, B., Benham, A., Nguyen, J., Valenzuela, N., Wu, H. J., Burns, A. R., Rasmussen, T. L., Tucker, H. O., & Schwartz, R. J. (2016). Mouse myofibers lacking the SMYD1 methyltransferase are susceptible to atrophy, internalization of nuclei and myofibrillar disarray. Disease Models & Mechanisms, 9, 347–359.
Stincone, A., Prigione, A., Cramer, T., Wamelink, M. M., Campbell, K., Cheung, E., Olin-Sandoval, V., Gruning, N. M., Kruger, A., Tauqeer Alam, M., Keller, M. A., Breitenbach, M., Brindle, K. M., Rabinowitz, J. D., & Ralser, M. (2015). The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biological Reviews of the Cambridge Philosophical Society, 90, 927–963.
Tanaka, Y., Eda, H., Fujimoto, K., Tanaka, T., Ishikawa, T., & Ishitsuka, H. (1990). Anticachectic activity of 5’-deoxy-5-fluorouridine in a murine tumor cachexia model, colon 26 adenocarcinoma. Cancer Research, 50, 4528–4532.
Tisdale, M. J., & Dhesi, J. K. (1990). Inhibition of weight loss by omega-3 fatty acids in an experimental cachexia model. Cancer Research, 50, 5022–5026.
Wang, Q., Liu, D., Song, P., & Zou, M. H. (2015). Tryptophan-kynurenine pathway is dysregulated in inflammation, and immune activation. Frontiers in Bioscience (Landmark Ed), 20, 1116–1143.
Xiao, N., Yang, L. L., Yang, Y. L., Liu, L. W., Li, J., Liu, B., Liu, K., Qi, L. W., & Li, P. (2017). Ginsenoside Rg5 inhibits succinate-associated lipolysis in adipose tissue and prevents muscle insulin resistance. Frontiers in Pharmacology, 8, 43.
Xu, Q., Brabham, J. G., Zhang, S., Munster, P., Fields, K., Zhao, R. J., & Yu, H. (2005). Chinese herbal formula, Bing De Ling, enhances antitumor effects and ameliorates weight loss induced by 5-fluorouracil in the mouse CT26 tumor model. DNA and Cell Biology, 24, 470–475.
Yennurajalingam, S., Tannir, N. M., Williams, J. L., Lu, Z., Hess, K. R., Frisbee-Hume, S., House, H. L., Lim, Z. D., Lim, K. H., Lopez, G., Reddy, A., Azhar, A., Wong, A., Patel, S. M., Kuban, D. A., Kaseb, A. O., Cohen, L., & Bruera, E. (2017). A double-blind, randomized, placebo-controlled trial of panax ginseng for cancer-related fatigue in patients with advanced cancer. Journal of the National Comprehensive Cancer Network, 15, 1111–1120.
Acknowledgements
We thank the metabolomics core at the convergence medicine research center, asan medical center, for their support and instrumentation.
Funding
This study was supported by grants from the Asan Institute of Life Sciences, Asan Medical Center, Republic of Korea (2017IL0540, 2018IL0540); from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2017R1A2B3007567); from the Industrial Core Technology Development Program (10063475) funded by the Ministry of Trade, Industry and Energy (Korea); and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (HI14C1090).
Author information
Authors and Affiliations
Contributions
HK: performed study design, animal experiments, sample preparation, data acquisition and analysis, and wrote the manuscript. SJK: acquired/interpreted the LC/MS–MS data. CW and SK: acquired/interpreted MRI data. ML, SKP, and JK: performed data analysis and edited the manuscript. HJY, DW, and JKK: oversaw all aspects of the research project and co-wrote the manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
All authors declare that he/she has no conflict of interest.
Ethical approval
This study was reviewed and approved by the Institutional Animal Care and Use Committee of the Asan Medical Institute of Convergence Science and Technology, Seoul, Korea (IACUC number: 2017-01-050). All procedures were performed according to the relevant guidelines of the National Cancer Institute.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Kim, Hj., Kim, S.J., Woo, CW. et al. Treatment of chemotherapy-induced cachexia with BST204: a multimodal validation study. Metabolomics 17, 36 (2021). https://doi.org/10.1007/s11306-021-01781-8
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11306-021-01781-8