Therapeutic Potential and Biological Applications of Cordycepin and Metabolic Mechanisms in Cordycepin-Producing Fungi

Abstract

Cordycepin(3'-deoxyadenosine), a cytotoxic nucleoside analogue found in Cordyceps militaris, has attracted much attention due to its therapeutic potential and biological value. Cordycepin interacts with multiple medicinal targets associated with cancer, tumor, inflammation, oxidant, polyadenylation of mRNA, etc. The investigation of the medicinal drug actions supports the discovery of novel targets and the development of new drugs to enhance the therapeutic potency and reduce toxicity. Cordycepin may be of great value owing to its medicinal potential as an external drug, such as in cosmeceutical, traumatic, antalgic and muscle strain applications. In addition, the biological application of cordycepin, for example, as a ligand, has been used to uncover molecular structures. Notably, studies that investigated the metabolic mechanisms of cordycepin-producing fungi have yielded significant information related to the biosynthesis of high levels of cordycepin. Here, we summarized the medicinal targets, biological applications, cytotoxicity, delivery carriers, stability, and pros/cons of cordycepin in clinical applications, as well as described the metabolic mechanisms of cordycepin in cordycepin-producing fungi. We posit that new approaches, including single-cell analysis, have the potential to enhance medicinal potency and unravel all facets of metabolic mechanisms of cordycepin in Cordyceps militaris.

Keywords: biological value; cordycepin; medicinal targets; metabolic mechanisms.

Figure 1

Cellular targets of cancer affected by cordycepin via various signal pathways. Note: A1R: adenosine A1 receptor. A3R: adenosine A3 receptor. GPCR: G protein-coupled receptor. TJA: tight junction activity. IL: interleukin. SOD: Superoxide Dismutase. NOS:nitric oxide synthase. CHK1: Checkpoint kinase 1. GPX: Glutathione peroxidase. EGFR: epidermal growth factor receptor. AVOs: acidic vesicular organelles. P-: phosphorylated. MMPs: matrix metalloproteinases, such as MMP-2 and MMP-9. AP-1 and NF-κB: transcription factors that bind to the promoter of MMP-9 gene and play an important role in regulating MMP-9 [15]. LC3-II: an autophagosome marker, and the cytoplasmic form LC3-I (18 kDa) is converted to LC3-II during autophagy [16]. DR3: death receptor3. TPA: 12-O-tetradecanoylpho-bol-13-acetate. PARP: Poly (adenosine-diphosphate-ribose) polymerase. HC: histopathology condition. HIF-1α: hypoxia-inducible factor 1α. MDR: multiple drug resistant. AMPK: adenosine 5′-monophosphate-activated protein kinase. MD: mitochondrial disfunction. The blue numbers in square brackets represent references associated with in vivo results. These abbreviations are also used in this paper.

Figure 2

Cellular targets of tumor affected by cordycepin via various signal pathways. Note: ROS: reactive oxygen species. C/EBPβ: CCAAT/enhancer binding protein β, which can bind to BZLF1 promoter and activate the transcription of BZLF1 [17]. MD: mitochondrial disfunction. These abbreviations are also used in this paper.

Figure 3

Anti-inflammatory and anti-oxidant targets affected by cordycepin via various signal pathways. Note: SOD: superoxide dismutase. GSH-Px: glutathione peroxidase. MDA: malondialdehyde. 6-OHDA-INT:6-hydroxydopamine-induced neurotoxicity. VC: Vitamin C. VE: Vitamin E. IL-1β: interleukin-1 beta. iNOS: inducible nitric oxide synthase. PGE2: prostaglandin E2. NO: nitric oxide. COX-2: cyclo-oxygenase. NF-κB: nuclear factor kappa-B. iNOS: inducible nitric oxide synthase. IgE: immunoglobulin E. ICAM-1: intercellular cell adhesion molecule-1. HO-1: heme oxygenase-1. These abbreviations are also used in this paper.

Figure 4

Other medicinal value and biological applications. Note: COR can also inhibit excitatory synaptic transmission [18] and have neuroprotective effects [19]. ER-COR has antiplatelet effects [20]. The [α-32P]-COR-TP is used for 3′-end radiolabeled RNA fragments [21].