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The Role of Cordycepin in Tumor Therapy and SARS-CoV-2

Introduction by Dr.med. Matthias Kraft

Cordyceps is the largest and most diverse genus in the family Ascomycota (sac fungi). It thrives in the humid forests of temperate and tropical zones and is widely distributed across Europe, North America, and East and Southeast Asia, particularly in Bhutan, China, Japan, Nepal, Korea, Thailand, Vietnam, Tibet, and the Himalayan regions of Indiaincluding Sikkim.

Cordyceps is a well-known parasitic fungus, feeding on insects and other arthropods from ten different orders. Over 200 bioactive compounds have been extracted from Cordyceps species, including nucleotides and nucleosides, polysaccharides, proteins and polypeptides, amino acids, sterols, fatty acids, and trace elements, highlighting the genus’ rich phytochemical profile.

These compounds are linked to numerous pharmacological effects, including:

• Antimicrobial
• Anti-apoptotic
• Anticancer
• Anti-inflammatory
• Antioxidant
• Immunomodulatory activities

This paper focuses on the bioactivity of the key compound cordycepin, with special emphasis on its potential application in tumor therapy.

Cordycepin – General Overview

Cordyceps species from the Ascomycota group (family Cordycipitaceae) have long been used in traditional Asian medicine to reduce fatigue and stimulate the immune system.

Cordyceps militaris (scarlet caterpillar fungus) grows on soil-dwelling larvae and pupae. Analysis of the fruiting bodies and mycelium has revealed several bioactive compounds such as:

• γ-Aminobutyric acid (GABA)
• Ergothioneine
• Sterols (e.g., ergosterol)
• Statins (e.g., lovastatin)
• Phenolic compounds (including phenolic acids and flavonoids)
• Vitamins and trace elements, notably selenium, which is present in organic forms such as selenomethionineand selenocysteine.

Newly identified components such as Cordyrrol A and B have shown metabolic regulatory effects in humans. Cordycepin (3′-deoxyadenosine), one of the hallmark compounds of C. militaris, is a structural analog of the nucleoside adenosine. It occurs either in free form or as a glycoside bound to a saccharide unit.

Pharmacological Effects and Clinical Studies

Recent in vitro and in vivo studies on C. militaris have shown cordycepin to possess:

• Antitumor
• Immunostimulatory
• Anti-inflammatory
• Antiviral
• Ergogenic (performance-enhancing) effects

It has been demonstrated that C. militaris induces apoptosis in ovarian carcinoma cells, accompanied by increased levels of TNF-α, TNFR1, NF-κB, caspase-3, and caspase-9, and decreased expression of Bcl-2 and Bcl-xL. The antitumor potential of cordycepin and its derivatives (e.g., NUC-7738) has also been confirmed in preclinical and clinical studies.

In a human study, healthy Korean men who took 1.5g of C. militaris daily for 4 weeks showed increased serum levels of IL-2, IL-12, TNF-α, IFN-γ, and natural killer cells, indicating immune activation. Similar effects were seen in piglets fed with 2g of C. militaris per kg of feed: increased IgA and IgG, and improved antioxidant status (higher glutathione peroxidase, lower MDA levels).

Cordycepin and COVID-19

Indian research suggests that cordycepin has potential efficacy against COVID-19, showing strong chemical interactions with SARS-CoV-2. In the context of fatigue and post-COVID syndrome, both animal studies and clinical experiences indicate that daily intake of Cordyceps may alleviate chronic fatigue symptoms.

A 12-week animal study found that mice fed with C. militaris extract (2.33 mg/g cordycepin) showed improved physical performance. This was associated with increased ATP production, AMPK activation, and higher phosphocreatine levels.

During the 1993 Olympic Games, Cordyceps gained attention for improving performance in athletes, especially runners. However, prospective human studies on endurance sports supplementation with Cordyceps have shown no significant performance increase.

A pilot study in patients with benign prostatic hyperplasia (BPH) found that C. militaris (capsule form) improved urinary flow, reduced prostate symptoms, and decreased prostate size.

Bioavailability and Challenges in Therapy

Despite promising effects, bioavailability remains a challenge for oral cordycepin. It has a short half-life (1.6 min), high plasma clearance, low permeability, and is subject to significant first-pass liver metabolism. Furthermore, its negative charge may impair cellular uptake.

Animal studies (e.g., Lee et al.) showed that intact cordycepin is not absorbed gastrointestinally, though its metabolite 3′-deoxyinosine was detected in the bloodstream. This metabolite can also form the active compound cordycepin-5′-triphosphate, suggesting a nucleoside salvage pathway may account for some effects post-oral administration.

Interestingly, the cytostatic drug pentostatin, which deaminates cordycepin, is naturally produced by C. militaris as a self-defense mechanism. Adding pentostatin to Cordyceps preparations has been shown to increase cordycepin absorption, likely due to improved metabolism.

Conclusion

Cordycepin is a highly promising natural compound with a broad spectrum of pharmacological activities, particularly in the contexts of tumor therapy and SARS-CoV-2. While oral bioavailability presents a challenge, new insights into metabolic pathways and formulation strategies may significantly improve its therapeutic efficacy.