Harnessing cordycepin’s therapeutic potential: A review with special focus on breast cancer

Cordycepin (CD), 3′- deoxy adenosine, is a major bioactive compound secreted by the entomopathogenic fungus Cordyceps militaris and Cordyceps sinensis. Cordyceps sinensis is known as DongChongXiaCa in Traditional Chinese Medicine (TCM). It possesses various pharmacological properties such as anti-inflammatory, immunomodulatory, anti-tumor activities. It also alleviates fatigue. Its therapeutic potential extends from cancer to several metabolic disorders. The therapeutic efficacy of CD in preclinical breast cancer (BC) studies has been highlighted with a focus on molecular pathways modulated by the compound. A systematic literature search was conducted across various electronic databases such as Google Scholar and PubMed in order to identify the relevant in vitro and in vivo studies. The chosen articles focused on the molecular mechanisms modulated by CD in BC and in other cancers. Articles related to therapeutic effects of CD against metabolic disorders, synergistic mechanisms with conventional treatments, bioavailability and pharmacokinetic limitations, clinical prospects and challenges of CD were also retrieved. Pre-clinical studies reported that CD possesses broad spectrum of biological properties, such as anti-tumor, anti-aging, anti-hyperlipidemic, inhibition of fat accumulation, reduction of body weight, anti-viral, anti-SARS-CoV-2, anti-hyperglycemic and skin-lightening properties . In vitro and in vivo studies highlighted the anti-cancer property of CD against BC. It covers the molecular pathways modulated by the natural compound in BC. CD induced apoptosis by upregulating Bax/BcL ratio, cleaved caspases 8 and 7 and downregulating BcL-2 in BC cell lines as well as in Triple Negative Breast Cancer (TNBC) xenograft models. It initiated autophagy in MCF-7 cells and apoptosis in MDA-MB-231 cells. CD inhibited cell invasion and metastasis by downregulating matrix metalloproteinases (MMP’s), epithelial-mesenchymal transition (EMT) markers in TNBC xenograft model. It also downregulated EMT transcription factors in TNBC cancer cell lines, inhibited markers of hedgehog signaling pathway. Several other BC molecular pathways regulated by CD are also covered. Apart from anti-BC activity, it also possesses anti-hyperlipidemic, anti-hyperglycemic, immunomodulatory, anti-obesity, anti-pigmentation, anti-anxiety, stress lowering, and anti-hypertensive properties. Pre-clinical studies on CD’s anti-cancer activity against colon, hepatocellular, leukemia and other cancers have been included. It displayed synergistic effects when combined with conventional chemotherapeutic drugs, including doxorubicin, cisplatin, gemcitabine and apatinib. One of the major limitations of CD is the bioavailability of the compound inside the human body. As CD is susceptible to degradation by adenosine deaminase (ADA) enzyme and its half-life is short, several studies have focused on enhancing the stability and bioavailability of the compound. Strategies such as encapsulation into polymeric nanoparticles, hybrid nanocarrier technologies, CD derivatives synthesis has greatly improved the bioavailability, stability and therapeutic ability of CD. CD, a bioactive compound found in Cordyceps species, have been employed in TCM for several hundred years. It exhibits anti-cancer activity against BC by modulating multiple BC signaling pathways. It also exhibits synergistic ability with numerous conventional cancer drugs. Although several in vitro and in vivo studies report its broad-spectrum therapeutic abilities, studies on its safety, possible drug interactions, translational potential into clinical settings are limited. Only few clinical trials have been conducted which investigates its translational therapeutic efficacy in humans. Complete molecular mechanisms responsible for its anti-cancer activity needs to be uncovered. Future research directions must focus on the above-mentioned aspects.