Open Access Open Access  Restricted Access Subscription or Fee Access

Anti-Cancer Effect of Cordyceps Militaris

Monika Devi


Cordyceps militaris is a therapeutic fungus that has been used for traditional herbal remedies. It contains variety of bioactive elements, including cordycepin. Cordycepin (3’-deoxyadenosine), is the main compound and is believed to have anti-cancer potential. Treatment of various cancer cells with cordycepin effectively causes cell death and slows down the nature of the cancer. But yet, the underlying mechanism is not fully understood. Recent findings provide information about molecular signalling pathways such as cysteine-aspartic proteases (caspases), mitogen-stimulated protein kinases (MAPKs), and glycogen synthase kinase 3 beta (GSK-3β). It also changes the reputation of receptors, such as adenosine receptors (ADORAs), death receptors (DRs), and the epidermal growth factor receptor (EGFR). This review gives an idea about the molecular mechanisms by which cordycepin acts as a singular or combinational anticancer therapeutic agent.


Cordyceps militaris, cordycepin, anti-cancer, adenosine receptors, death receptors, apoptosis

Full Text:



Wasser SP. Medicinal Mushrooms as a Source of Antitumor and Immunomodulating

Polysaccharides. Appl Microbiol Biotechnol. 2002; 60(3): 258–274p.

Anderson BO, Flanigan J. Novel Methods for Measuring Global Cancer Burden: Implications for

Global Cancer Control. JAMA Oncol. 2015; 1(4): 425–427p.

Shklar G. Development of Experimental Oral Carcinogenesis and Its Impact on Current Oral

Cancer Research. J Dent Res. 1999; 78(12): 1768–72p.

Ribeiro JA. Purinergic Inhibition of Neurotransmitter Release in the Central Nervous System.

Pharmacol Toxicol. 1995; 77(5): 299–305p.

Tian X, Li Y, Shen Y, Li Q, Wang Q, Feng L. Apoptosis and Inhibition of Proliferation of Cancer

Cells Induced by Cordycepin. Oncol Lett. 2015; 10(2): 595–599p.

Cunningham KG, Hutchinson SA, Manson W, Spring FS. Cordycepin, a Metabolic Product from

Cultures of Cordyceps militaris (Linn.) Link. Part I. Isolation and Characterization. J Chem Soc.

; (0): 2299–2300p.

Paterson RRM. Cordyceps- Traditional Chinese Medicine and Another Fungal Therapeutic

Biofactory? Phytochemistry. 2008; 69(7): 1469–1495p.

Wang M, Meng X, Yang R, et al. Cordyceps militaris Polysaccharides can Improve the Immune

Efficacy of Newcastle Disease Vaccine in Chicken. Int J Biol Macromol. 2013; 59: 178–83p.

Kitakaze M, Hori M. Adenosine Therapy: A New Approach to Chronic Heart Failure. Expert Opin

Investig Drugs. 2000; 9(11): 2519–35p.

Li SP, Yang FQ, Tsim KW. Quality Control of Cordyceps Sinesis, a Valued Traditional Chinese

Medicine. J Pharma Biomed Anal. 2006; 41(5): 1571–84p.

Jeong J-W, Jin C-Y, Park et al. Induction of Apoptosis by Cordycepin via Reactive Oxygen Species

Generation in Human Leukemia Cells. Toxicol In Vitro. 2011; 25(4): 817–824p.

Sheth S, Brito R, Mukherjea D, Rybak LP, Ramkumar V. Adenosine Receptors: Expression,

Function and Regulation. Int J Mol Sci. 2014; 15(2): 2024–2052p.

Kuchta RD. Nucleotide Analogues as Probes for DNA and RNA Polymerases. Curr Protocols Chem Biol. 2010; 2(2): 111–124p.

Klenow H. Formation of the Mono-, Di-and Triphosphate of Cordycepin in Ehrlich Ascites-Tumor Cells in vitro. Biochim Biophys Acta. 1963; 76: 347–353p.

Holbein S, Wengi A, Decourty L, Freimoser FM, Jacquier A, Dichtl B. Cordycepin Interferes with

’ End Formation in Yeast Independently of Its Potential to Terminate RNA Chain Elongation. RNA. 2009; 15(5): 837–849p.

Horowitz B, Goldfinger BA, Marmur J. Effect of Cordycepin Triphosphate on the Nuclear DNADependent RNA Polymerases and Poly (A) Polymerase from the Yeast, Saccharomyces cerevisiae. Arch Biochem Biophys. 1976; 172(1): 143–148p.

Müller WE, Seibert G, Beyer R, Breter HJ, Maidhof A, Zahn RK. Effect of Cordycepin on Nucleic Acid Metabolism in L5178Y Cells and on Nucleic Acid-Synthesizing Enzyme Systems. Cancer Res. 1977; 37(10): 3824–3833p.

Rottman F, Guarino AJ. The Inhibition of Phosphoribosyl-Pyrophosphate Amidotransferase

Activity by Cordycepin Monophosphate. Biochim Biophys Acta. 1964; 89(3): 465–472p.

Chen Y, Yang S-H, Hueng D-Y, Syu J-P, Liao C-C, Wu Y-C. Cordycepin Induces Apoptosis of C6 Glioma Cells through the Adenosine 2A Receptor-p53-Caspase-7-PARP Pathway. Chem-Biol Interact. 2014; 216: 17–25p.

Cao H-L, Liu Z-J, Chang Z. Cordycepin Induces Apoptosis in Human Bladder Cancer Cells via Activation of A3 Adenosine Receptors. Tumor Biol. 2017; 39(7): 1010428317706915p.

Nakamura K, Yoshikawa N, Yamaguchi Y, Kagota S, Shinozuka K, Kunitomo M. Antitumor Effect of Cordycepin (3’-Deoxyadenosine) on Mouse Melanoma and Lung Carcinoma Cells Involves

Adenosine A3 Receptor Stimulation. Anticancer Res. 2006; 26(1 A): 43–47p.

Yoshikawa N, Yamada S, Takeuchi C, Kagota S, Shinozuka K, Kunitomo M, Nakamura K.

Cordycepin (3’-Deoxyadenosine) Inhibits the Growth of B16-BL6 Mouse Melanoma Cells through the Stimulation of Adenosine A3 Receptor Followed by Glycogen Synthase Kinase-3β Activation and Cyclin D1 Suppression. Naunyn-Schmiedeberg’s Arch Pharmacol. 2008; 377(4–6): 591–595p.

Lee SY, Debnath T, Kim S-K, Lim BO. Anti-Cancer Effect and Apoptosis Induction of Cordycepin through DR3 Pathway in the Human Colonic Cancer Cell HT-29. Food Chem Toxicol. 2013; 60:


Lee HH, Kim SO, Kim et al. Involvement of Autophagy in Cordycepin-Induced Apoptosis in

Human Prostate Carcinoma LNCaP Cells. Environ Toxicol Pharmacol. 2014; 38(1): 239–250p.

Liao Y, Ling J, Zhang G, Liu F, Tao S, Han Z, Chen S, Chen Z, Le H. Cordycepin Induces Cell

Cycle Arrest and Apoptosis by Inducing DNA Damage and Up-Regulation of p53 in Leukemia

Cells. Cell Cycle. 2015; 14(5): 761–771p.

McIlwain DR, Berger T, Mak TW. Caspase Functions in Cell Death and Disease. Cold Spring

Harbor Perspect Biol. 2013; 5(4): a008656p.

Choi S, Lim M-H, Kim KM, Jeon BH, Song WO, Kim TW. Cordycepin-Induced Apoptosis and

Autophagy in Breast Cancer Cells are Independent of the Estrogen Receptor. Toxicol Appl

Pharmacol. 2011; 257(2): 165–173p.

Cai J, Yang J, Jones D. Mitochondrial Control of Apoptosis: The Role of Cytochrome C. Biochim

Biophys Acta. 1998; 1366(1–2): 139–149p.

Tao X, Ning Y, Zhao X, Pan T. The Effects of Cordycepin on the Cell Proliferation, Migration and

Apoptosis in Human Lung Cancer Cell Lines A549 and NCI-H460. J Pharm Pharmacol. 2016;

(7): 901–911p.

Shao LW, Huang LH, Yan S, Jin JD, Ren SY. Cordycepin Induces Apoptosis in Human Liver

Cancer HepG2 Cells through Extrinsic and Intrinsic Signaling Pathways. Oncol Lett. 2016; 12(2):


Wang D, Zhang Y, Lu J, Wang Y, Wang J, Meng Q, Lee RJ, Teng L. Cordycepin, a Natural

Antineoplastic Agent, Induces Apoptosis of Breast Cancer Cells via Caspase-Dependent Pathways.

Nat Prod Commun. 2016; 11(1): 63–68p.

Kim H, Naura AS, Errami Y, Ju J, Boulares AH. Cordycepin Blocks Lung Injury-Associated

Inflammation and Promotes BRCA1-Deficient Breast Cancer Cell Killing by Effectively Inhibiting

PARP. Mol Med. 2011; 17(9–10): 893p.

Yamamoto K, Shichiri H, et al. Apoptotic Effects of the Extracts of Cordyceps militaris via Erk

Phosphorylation in a Renal Cell Carcinoma Cell Line. Phytother Res. 2015; 29(5): 707–713p.

Jeong J-W, Jin C-Y, et al. Induction of Apoptosis by Cordycepin via Reactive Oxygen Species

Generation in Human Leukemia Cells. Toxicol In Vitro. 2011; 25(4): 817–824p.

Tian T, Song L, Zheng Q, Hu X, Yu R. Induction of Apoptosis by Cordyceps militaris Fraction in

Human Chronic Myeloid Leukemia K562 Cells Involved with Mitochondrial Dysfunction. Pharm

Mag. 2014; 10(39): 325p.

Li Y, Li R, Zhu S, et al. Cordycepin Induces Apoptosis and Autophagy in Human Neuroblastoma

SK-N-SH and BE (2)-M17 Cells. Oncol Lett. 2015; 9(6): 2541–2547p.

Baik J-S, Kwon H-Y, Kim K-S. Cordycepin Induces Apoptosis in Human Neuroblastoma SK-NBE (2)-C and Melanoma SK-MEL-2 Cells. Indian J Biochem Biophys. 2012; 49(2): 86–91p.

Gessi S, Merighi S, Sacchetto V, Simioni C, Borea PA. Adenosine Receptors and Cancer. Biochim

Biophys Acta. 2011; 1808(5): 1400–1412p.

Antonioli L, Fornai M, Blandizzi C, Pacher P, Haskó G. Adenosine Signalling and the Immune

System: When a lot could be too much. Immunol Lett. 2019; 205: 9–15p.

Fredholm BB, IJzerman AP, Jacobson KA, Klotz K-N, Linden J. International Union of

Pharmacology. XXV. Nomenclature and Classification of Adenosine Receptors. Pharmacol Rev.

; 53(4): 527–552p.

Ramkumar V, Stiles G, Beaven M, Ali H. The A3 Adenosine Receptor is the Unique Adenosine

Receptor which Facilitates Release of Allergic Mediators in Mast Cells. J Biol Chem. 1993;

(23): 16887–16890p. [PubMed]

Ali H, Müller C, Daly JW, Beaven MA. Methylxanthines Block Antigen-Induced Responses in

RBL-2H3 Cells Independently of Adenosine Receptors or Cyclic AMP: Evidence for Inhibition of

Antigen Binding to IgE. J Pharmacol Exp Ther. 1991; 258(3): 954–962p.

Waldo GL, Ricks TK, et al. Kinetic Scaffolding Mediated by a Phospholipase C–β and Gq

Signaling Complex. Science. 2010; 330(6006): 974–980p.

Brown S-A, Morgan F, Watras J, Loew LM. Analysis of Phosphatidylinositol-4, 5-Bisphosphate

Signaling in Cerebellar Purkinje Spines. Biophys J. 2008; 95(4): 1795–1812p.

Pao H-Y, Pan B-S, Leu S-F, Huang B-M. Cordycepin Stimulated Steroidogenesis in MA-10 Mouse

Leydig Tumor Cells through the Protein Kinase C Pathway. J Agric Food Chem. 2012; 60(19):


Lee S-J, Kim S-K, Choi W-S, Kim W-J, Moon S-K. Cordycepin Causes p21WAF1-Mediated G2/M

Cell-Cycle Arrest by Regulating c-Jun N-Terminal Kinase Activation in Human Bladder Cancer

Cells. Arch Biochem Biophys. 2009; 490(2): 103–109p.

Milella M, Kornblau SM, et al. Therapeutic Targeting of the MEK/MAPK Signal Transduction

Module in Acute Myeloid Leukemia. J Clin Investig. 2001; 108(6): 851–859p.

Hwang J-H, Joo JC, et al. Cordycepin Promotes Apoptosis by Modulating the ERK-JNK Signaling

Pathway via DUSP5 in Renal Cancer Cells. Am J Cancer Res. 2016; 6(8): 1758p.

Joo JC, Hwang JH, et al. Cordycepin Induces Apoptosis by Caveolin-1-Mediated JNK Regulation

of Foxo3a in Human Lung Adenocarcinoma. Oncotarget. 2017; 8(7): 12211p.

Hwang JH, Park SJ, et al. Cordycepin Induces Human Lung Cancer Cell Apoptosis by Inhibiting

Nitric Oxide Mediated ERK/Slug Signaling Pathway. Am J Cancer Res. 2017; 7(3): 417–432p.

Baik J-S, Mun S-W, et al. Apoptotic Effects of Cordycepin through the Extrinsic Pathway and p38

MAPK Activation in Human Glioblastoma U87MG Cells. J Microbiol Biotechnol. 2016; 26(2):


Ko B-S, Lu Y-J, Yao W-L, Liu T-A, Tzean S-S, Shen T-L, Liou J-Y. Cordycepin Regulates GSK3β/β-Catenin Signaling in Human Leukemia Cells. PLoS ONE. 2013; 8(9): e76320p.

Fresno JV, Casado E, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt Signalling Pathway and Cancer. Cancer Treat Rev. 2004; 30(2): 193–204p.

Wang Z, Wu X, Liang Y-N, Wang L, Song Z-X, Liu J-L, Tang Z-S. Cordycepin Induces Apoptosis

and Inhibits Proliferation of Human Lung Cancer Cell Line H1975 via Inhibiting the Phosphorylation of EGFR. Molecules. 2016; 21(10): 1267p.

Fishman P, Bar-Yehuda S, Liang BT, Jacobson KA. Pharmacological and Therapeutic Effects of

A3 Adenosine Receptor Agonists. Drug Discov Today. 2012; 17(7–8): 359–366p.

Robinson DR, Wu Y-M, et al. Integrative Clinical Genomics of Metastatic Cancer. Nature. 2017; 548: 297–303p.

Nakamura K, Shinozuka K, Yoshikawa N. Anticancer and Antimetastatic Effects of Cordycepin,

an Active Component of Cordyceps sinensis. J Pharm Sci. 2015; 127(1): 53–56p.

Noh E-M, Jung SH, et al. Cordycepin Inhibits TPA-Induced Matrix Metalloproteinase-9

Expression by Suppressing the MAPK/AP-1 Pathway in MCF-7 Human Breast Cancer Cells. Int J

Mol Med. 2010; 25(5): 255–260p.

Ma Y-HV, Middleton K, You L, Sun Y. A Review of Microfluidic Approaches for Investigating

Cancer Extravasation during Metastasis. Microsyst Nanoeng. 2018; 4: 17104p.


  • There are currently no refbacks.

Copyright (c) 2020 Research & Reviews A Journal of Pharmacognosy