Abstract
Chemotherapy-related fatigue (CRF) is increasingly being recognized as one of the severe symptoms in patients undergoing chemotherapy, which not only largely reduces the quality of life in patients, but also diminishes their physical and social function. At present, there is no effective drug for preventing and treating CRF. Ganoderic acid (GA), isolated from traditional Chinese medicine Ganoderma lucidum, has shown a variety of pharmacological activities such as anti-tumor, anti-inflammation, immunoregulation, etc. In this study, we investigated whether GA possessed anti-fatigue activity against CRF. CT26 tumor-bearing mice were treated with 5-fluorouracil (5-FU, 30 mg/kg) and GA (50 mg/kg) alone or in combination for 18 days. Peripheral and central fatigue-related behaviors, energy metabolism and inflammatory factors were assessed. We demonstrated that co-administration of GA ameliorated 5-FU-induced peripheral muscle fatigue-like behavior via improving muscle quality and mitochondria function, increasing glycogen content and ATP production, reducing lactic acid content and LDH activity, and inhibiting p-AMPK, IL-6 and TNF-α expression in skeletal muscle. Co-administration of GA also retarded the 5-FU-induced central fatigue-like behavior accompanied by down-regulating the expression of IL-6, iNOS and COX2 in the hippocampus through inhibiting TLR4/Myd88/NF-κB pathway. These results suggest that GA could attenuate 5-FU-induced peripheral and central fatigue in tumor-bearing mice, which provides evidence for GA as a potential drug for treatment of CRF in clinic.
Similar content being viewed by others
Login or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394:1467–80.
Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383:1490–502.
Lee JJ, Beumer JH, Chu E. Therapeutic drug monitoring of 5-fluorouracil. Cancer Chemother Pharmacol. 2016;78:447–64.
McQuade RM, Stojanovska V, Bornstein JC, Nurgali K. Colorectal cancer chemotherapy: the evolution of treatment and new approaches. Curr Med Chem. 2017;24:1537–57.
Iacovelli R, Pietrantonio F, Maggi C, de Braud F, Di, Bartolomeo M. Combination or single-agent chemotherapy as adjuvant treatment of gastric cancer: A systematic review and meta-analysis of published trials. Crit Rev Oncol Hematol. 2016;98:24–8.
Dougherty JP, Springer DA, Cullen MJ, Gershengorn MC. Evaluation of the effects of chemotherapy-induced fatigue and pharmacological interventions in multiple mouse behavioral assays. Behav Brain Res. 2019;360:255–61.
Chakravarthy AB, Zhao F, Meropol NJ, Flynn PJ, Wagner LI, Sloan J, et al. Intergroup randomized phase III study of postoperative oxaliplatin, 5-fluorouracil, and leucovorin versus oxaliplatin, 5-fluorouracil, leucovorin, and bevacizumab for patients with stage II or III rectal cancer receiving preoperative chemoradiation: A trial of the ECOG-ACRIN research group (E5204). Oncologist. 2020;25:e798–e807.
Chibaudel B, Bachet JB, André T, Auby D, Desramé J, Deplanque G, et al. Efficacy of aflibercept with FOLFOX and maintenance with fluoropyrimidine as first‑line therapy for metastatic colorectal cancer: GERCOR VELVET phase II study. Int J Oncol. 2019;54:1433–45.
Husson O, Nieuwlaat WA, Oranje WA, Haak HR, van de Poll-Franse LV, Mols F. Fatigue among short- and long-term thyroid cancer survivors: results from the population-based PROFILES registry. Thyroid. 2013;23:1247–55.
Bower JE, Lamkin DM. Inflammation and cancer-related fatigue: mechanisms, contributing factors, and treatment implications. Brain Behav Immun. 2013;30:S48–57.
Akin S, Kas Guner C. Investigation of the relationship among fatigue, self-efficacy and quality of life during chemotherapy in patients with breast, lung or gastrointestinal cancer. Eur J Cancer Care (Engl). 2019;28:e12898.
Xiao Z, Hu L, Lin J, Lu L, Huang X, Zhu X, et al. Efficacy and safety of Jianpishengsui for chemotherapy-related fatigue in patients with non-small cell lung cancer: study protocol for a randomized placebo-controlled clinical trial. Trials. 2020;21:94.
Vissers PA, Thong MS, Pouwer F, Zanders MM, Coebergh JW, van de Poll-Franse LV. The impact of comorbidity on health-related quality of life among cancer survivors: analyses of data from the PROFILES registry. J Cancer Surviv. 2013;7:602–13.
McMorris T, Barwood M, Corbett J. Central fatigue theory and endurance exercise: toward an interoceptive model. Neurosci Biobehav Rev. 2018;93:93–107.
Courneya KS, Segal RJ, Mackey JR, Gelmon K, Reid RD, Friedenreich CM, et al. Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial. J Clin Oncol. 2007;25:4396–404.
Neefjes ECW, van den Hurk RM, Blauwhoff-Buskermolen S, van der Vorst M, Becker-Commissaris A, de van der Schueren MAE, et al. Muscle mass as a target to reduce fatigue in patients with advanced cancer. J Cachexia Sarcopenia Muscle. 2017;8:623–9.
Ballarò R, Beltrà M, De Lucia S, Pin F, Ranjbar K, Hulmi JJ, et al. Moderate exercise in mice improves cancer plus chemotherapy-induced muscle wasting and mitochondrial alterations. FASEB J. 2019;33:5482–94.
Barreto R, Mandili G, Witzmann FA, Novelli F, Zimmers TA, Bonetto A. Cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. Front Physiol. 2016;7:472.
Pin F, Barreto R, Couch ME, Bonetto A, O’Connell TM. Cachexia induced by cancer and chemotherapy yield distinct perturbations to energy metabolism. J Cachexia Sarcopenia Muscle. 2019;10:140–54.
Bower JE. Cancer-related fatigue–mechanisms, risk factors, and treatments. Nat Rev Clin Oncol. 2014;11:597–609.
Weymann KB, Wood LJ, Zhu X, Marks DL. A role for orexin in cytotoxic chemotherapy-induced fatigue. Brain Behav Immun. 2014;37:84–94.
Yang S, Chu S, Gao Y, Ai Q, Liu Y, Li X, et al. A narrative review of cancer-related fatigue (CRF) and its possible pathogenesis. Cells. 2019;8:738.
O’Higgins CM, Brady B, O’Connor B, Walsh D, Reilly RB. The pathophysiology of cancer-related fatigue: current controversies. Support Care Cancer. 2018;26:3353–64.
van Vulpen JK, Schmidt ME, Velthuis MJ, Wiskemann J, Schneeweiss A, Vermeulen RCH, et al. Effects of physical exercise on markers of inflammation in breast cancer patients during adjuvant chemotherapy. Breast Cancer Res. Treat. 2018;168:421–31.
Barton DL, Liu H, Dakhil SR, Linquist B, Sloan JA, Nichols CR, et al. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst. 2013;105:1230–8.
Inglis JE, Lin PJ, Kerns SL, Kleckner IR, Kleckner AS, Castillo DA, et al. Nutritional interventions for treating cancer-related fatigue: a qualitative review. Nutr Cancer. 2019;71:21–40.
Ouyang M, Liu Y, Tan W, Xiao Y, Yu K, Sun X, et al. Bu-zhong-yi-qi pill alleviate the chemotherapy-related fatigue in 4 T1 murine breast cancer model. BMC Complement Alter Med. 2014;14:497.
Hsu CL, Yen GC. Ganoderic acid and lucidenic acid (triterpenoid). Enzymes. 2014;36:33–56.
Wang J, Cao B, Zhao H, Feng J. Emerging roles of Ganoderma Lucidum in anti-aging. Aging Dis. 2017;8:691–707.
Su L, Liu L, Jia Y, Lei L, Liu J, Zhu S, et al. Ganoderma triterpenes retard renal cyst development by downregulating Ras/MAPK signaling and promoting cell differentiation. Kidney Int. 2017;92:1404–18.
Zhong D, Wang H, Liu M, Li X, Huang M, Zhou H, et al. Ganoderma lucidum polysaccharide peptide prevents renal ischemia reperfusion injury via counteracting oxidative stress. Sci Rep. 2015;5:16910.
Meng J, Wang SZ, He JZ, Zhu S, Huang BY, Wang SY, et al. Ganoderic acid A is the effective ingredient of ganoderma triterpenes in retarding renal cyst development in polycystic kidney disease. Acta Pharmacol Sin. 2020;41:782–90.
Zhao H, Zhang Q, Zhao L, Huang X, Wang J, Kang X. Spore powder of ganoderma lucidum improves cancer-related fatigue in breast cancer patients undergoing endocrine therapy: a pilot clinical trial. Evid Based Complement Altern Med. 2012;2012:809614.
Gill BS, Navgeet, Kumar S. Ganoderma lucidum targeting lung cancer signaling: a review. Tumour Biol. 2017;39:1010428317707437.
Chi B, Wang S, Bi S, Qin W, Wu D, Luo Z, et al. Effects of ganoderic acid A on lipopolysaccharide-induced proinflammatory cytokine release from primary mouse microglia cultures. Exp Ther Med. 2018;15:847–53.
Sheng F, Zhang L, Wang S, Yang L, Li P. Deacetyl ganoderic acid F inhibits LPS-induced neural inflammation via NF-κB pathway both in vitro and In vivo. Nutrients. 2019;12:85.
Norden DM, Bicer S, Clark Y, Jing R, Henry CJ, Wold LE, et al. Tumor growth increases neuroinflammation, fatigue and depressive-like behavior prior to alterations in muscle function. Brain Behav Immun. 2015;43:76–85.
Yang M, Kim J, Kim JS, Kim SH, Kim JC, Kang MJ, et al. Hippocampal dysfunctions in tumor-bearing mice. Brain Behav Immun. 2014;36:147–55.
Lin DM, Wang SZ, Luo HJ, Lin ZX, Lin SQ. Rapid separation of ganoderic acid from the extraction by-products of Ganoderma lucidum. Fujian Med J. 2018;40:135–8.
Geng XQ, Ma A, He JZ, Wang L, Jia YL, Shao GY, et al. Ganoderic acid hinders renal fibrosis via suppressing the TGF-β/Smad and MAPK signaling pathways. Acta Pharmacol Sin. 2020;41:670–7.
Park HJ, Shim HS, Kim JY, Kim JY, Park SK, Shim I. Ginseng purified dry extract, BST204, improved cancer chemotherapy-related fatigue and toxicity in mice. Evid Based Complement Altern Med. 2015;2015:197459.
Dougherty JP, Wolff BS, Cullen MJ, Saligan LN, Gershengorn MC. Taltirelin alleviates fatigue-like behavior in mouse models of cancer-related fatigue. Pharmacol Res. 2017;124:1–8.
Han YH, Mun JG, Jeon HD, Yoon DH, Choi BM, Kee JY, et al. The extract of Arctium lappa L. fruit (Arctii Fructus) improves cancer-induced cachexia by inhibiting weight loss of skeletal muscle and adipose tissue. Nutrients. 2020;12:3195.
Yang F, Zhou L, Song J, WangJinMei A, Yang Y, Tang ZW, et al. Liver CEBPβ modulates the kynurenine metabolism and mediates the motility for hypoxia-induced central fatigue in mice. Front Physiol. 2019;10:243.
Wang X, Qu Y, Zhang Y, Li S, Sun Y, Chen Z, et al. Antifatigue potential activity of sarcodon imbricatus in acute excise-treated and chronic fatigue syndrome in mice via regulation of Nrf2-mediated oxidative stress. Oxid Med Cell Longev. 2018;2018:9140896.
Zhang X, Jing S, Lin H, Sun W, Jiang W, Yu C. et al. Anti-fatigue effect of anwulignan via the NRF2 and PGC-1α signaling pathway in mice. Food Funct. 2019;10:7755–66.
Zhou YT, Li SS, Ai M, Chen H, Liu YX, Li BY, et al. 1,25(OH)2D3 mitigate cancer-related fatigue in tumor-bearing mice: Integrating network pharmacological analysis. Biomed Pharmacother. 2020;128:110256.
Zhang Y, Li Z, Zhao Z, Kuai W, Wei C, Lv J, et al. Effect of the chinese medicine YangZheng XiaoJi on reducing fatigue in mice with orthotopic transplantation of colon cancer. Evid Based Complement Altern Med. 2019;2019:3870812.
Minton O, Alexander S, Stone PC. Identification of factors associated with cancer related fatigue syndrome in disease-free breast cancer patients after completing primary treatment. Breast Cancer Res Treat. 2012;136:513–20.
Gill BS, Sharma P, Kumar R, Kumar S. Misconstrued versatility of Ganoderma lucidum: a key player in multi-targeted cellular signaling. Tumour Biol. 2016;37:2789–804.
Powers SK, Lynch GS, Murphy KT, Reid MB, Zijdewind I. Disease-induced skeletal muscle atrophy and fatigue. Med Sci Sports Exerc. 2016;48:2307–19.
Grossberg AJ, Vichaya EG, Christian DL, Molkentine JM, Vermeer DW, Gross PS, et al. Tumor-associated fatigue in cancer patients develops independently of IL1 signaling. Cancer Res. 2018;78:695–705.
Rutherford G, Manning P, Newton JL. Understanding muscle dysfunction in chronic fatigue syndrome. J Aging Res. 2016;2016:2497348.
Shen Q, Miao C-X, Zhang W-L, Li Y-W, Chen Q-Q, Li X-X, et al. SiBaoChongCao exhibited anti-fatigue activities and ameliorated cancer cachexia in mice. RSC Adv. 2019;9:17440–56.
Niere M, Kernstock S, Koch-Nolte F, Ziegler M. Functional localization of two poly(ADP-ribose)-degrading enzymes to the mitochondrial matrix. Mol Cell Biol. 2008;28:814–24.
Liu R, Wu L, Du Q, Ren JW, Chen QH, Li D, et al. Small molecule oligopeptides isolated from Walnut (Juglans regia L.) and their anti-fatigue effects in mice. Molecules. 2018;24:45.
Li Y, Xin Y, Xu F, Zheng M, Xi X, Cui X, et al. Maca polysaccharides: extraction optimization, structural features and anti-fatigue activities. Int J Biol Macromol. 2018;115:618–24.
Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007;8:774–85.
Hardee JP, Montalvo RN, Carson JA. Linking cancer cachexia-induced anabolic resistance to skeletal muscle oxidative metabolism. Oxid Med Cell Longev. 2017;2017:8018197.
Carson JA, Hardee JP, VanderVeen BN. The emerging role of skeletal muscle oxidative metabolism as a biological target and cellular regulator of cancer-induced muscle wasting. Semin Cell Dev Biol. 2016;54:53–67.
VanderVeen BN, Fix DK, Carson JA. Disrupted skeletal muscle mitochondrial dynamics, mitophagy, and biogenesis during cancer cachexia: a role for inflammation. Oxid Med Cell Longev. 2017;2017:3292087.
White JP, Puppa MJ, Gao S, Sato S, Welle SL, Carson JA. Muscle mTORC1 suppression by IL-6 during cancer cachexia: a role for AMPK. Am J Physiol Endocrinol Metab. 2013;304:E1042–52.
Wong J, Smith LB, Magun EA, Engstrom T, Kelley-Howard K, Jandhyala DM, et al. Small molecule kinase inhibitors block the ZAK-dependent inflammatory effects of doxorubicin. Cancer Biol Ther. 2013;14:56–63.
Wood LJ, Weymann K. Inflammation and neural signaling: etiologic mechanisms of the cancer treatment-related symptom cluster. Curr Opin Support Palliat Care. 2013;7:54–9.
Casaril AM, Domingues M, Bampi SR, Lourenço DA, Smaniotto T, Segatto N, et al. The antioxidant and immunomodulatory compound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole attenuates depression-like behavior and cognitive impairment developed in a mouse model of breast tumor. Brain Behav Immun. 2020;84:229–41.
Dantzer R, Heijnen CJ, Kavelaars A, Laye S, Capuron L. The neuroimmune basis of fatigue. Trends Neurosci. 2014;37:39–46.
Morris G, Maes M. Oxidative and nitrosative stress and immune-inflammatory pathways in patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). Curr Neuropharmacol. 2014;12:168–85.
Shui L, Yi RN, Wu YJ, Bai SM, Si Q, Bo AG, et al. Effects of mongolian marm acupuncture on iNOS/NO and inflammatory cytokines in the hippocampus of chronic fatigue rats. Front Integr Neurosci. 2019;13:78.
Yuan R, Huang L, Du LJ, Feng JF, Li J, Luo YY, et al. Dihydrotanshinone exhibits an anti-inflammatory effect in vitro and in vivo through blocking TLR4 dimerization. Pharmacol Res. 2019;142:102–14.
Liu FY, Cai J, Wang C, Ruan W, Guan GP, Pan HZ, et al. Fluoxetine attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage: a possible role for the regulation of TLR4/MyD88/NF-κB signaling pathway. J Neuroinflammation. 2018;15:347.
Cleary JM, Mamon HJ, Szymonifka J, Bueno R, Choi N, Donahue DM, et al. Neoadjuvant irinotecan, cisplatin, and concurrent radiation therapy with celecoxib for patients with locally advanced esophageal cancer. BMC Cancer. 2016;16:468.
Norden DM, McCarthy DO, Bicer S, Devine RD, Reiser PJ, Godbout JP, et al. Ibuprofen ameliorates fatigue- and depressive-like behavior in tumor-bearing mice. Life Sci. 2015;143:65–70.
Zhu X, Burfeind KG, Michaelis KA, Braun TP, Olson B, Pelz KR, et al. MyD88 signalling is critical in the development of pancreatic cancer cachexia. J Cachexia Sarcopenia Muscle. 2019;10:378–90.
Chen MC, Hsu WL, Hwang PA, Chen YL, Chou TC. Combined administration of fucoidan ameliorates tumor and chemotherapy-induced skeletal muscle atrophy in bladder cancer-bearing mice. Oncotarget. 2016;7:51608–18.
Lee H, Heo JW, Kim AR, Kweon M, Nam S, Lim JS, et al. Z-ajoene from crushed garlic alleviates cancer-induced skeletal muscle atrophy. Nutrients. 2019;11:2724.
Irwin MR. Inflammation at the intersection of behavior and somatic symptoms. Psychiatr Clin North Am. 2011;34:605–20.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (grants 81620108029, 81974083, 81330074, 81500535 and 81800388), the Beijing Natural Science Foundation (grant 7212151), and the China Postdoctoral Science Foundation (grant 2018M630049).
Author information
Authors and Affiliations
Contributions
AA, BXY, and ML conceptualized and designed this study. AA, LH, AM, FYS, HZZ, SML, GYS, YX, JHR, JL, DML, and LFW performed the experiments and analyzed the data. AA and BXY wrote the paper. HZ, ML, and BXY reviewed and revised the paper.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Supplementary information
Rights and permissions
About this article
Cite this article
Abulizi, A., Hu, L., Ma, A. et al. Ganoderic acid alleviates chemotherapy-induced fatigue in mice bearing colon tumor. Acta Pharmacol Sin 42, 1703–1713 (2021). https://doi.org/10.1038/s41401-021-00669-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41401-021-00669-6
Keywords
This article is cited by
-
Identification of diagnostic biomarkers in prostate cancer-related fatigue by construction of predictive models and experimental validation
British Journal of Cancer (2025)
-
Bcl-xL DNAzymes promote radiosensitivity and chemosensitivity in colorectal cancer cells via enhancing apoptosis
BMC Pharmacology and Toxicology (2022)
