Cordycepin could be a promising candidate for the development of anticancer drugs targeting human brain cancers

Brain cancer, in particular neuroblastoma and glioblastoma, is global health problems and social issues. Among children and teens, brain cancer is the most common form of cancer and the leading cause of cancer death.

According to the American Cancer Society, in 2016, a brain cancer was diagnosed in almost 23,770 adults, and 16,050 adults died from it in the United States. Of the brain cancers, neuroblastoma is the most predominant extracranial solid cancer in infancy and childhood. Another fatal brain cancer is glioblastoma that is the most prevalent and aggressive malignant primary brain tumor with a median survival rate of only 12–15 months and occurrence of 3.19 per 100,000 people . Glioblastoma is exacerbated by its rapid growth and highly diffused infiltration. Therefore, patients with neuroblastoma and glioblastoma having 5-year survival rates were merely 59% and 5%, respectively.

 To date, anticancer agents extracted from natural sources have been widely applied to prevent and cure cancers . Anticancer agents exerted their activity against cancer cells by inducing several mechanisms of cell death, including apoptosis (type I cell death) and autophagy (type II cell death). Cordycepin, a major bioactive component found in insect fungus, Cordyceps spp., exhibits significant anticancer potential . Cordycepin is a derivative of the nucleoside adenosine, and its chemical formula is C10H13N5O3 with a molecular weight of 251.24 Da . The structure of cordycepin comprises an adenine nucleoside molecule, attached to a ribose sugar moiety via a β-N9-glycosidic bond.

The biological function of cordycepin has been explored for its anti-tumor and anti-inflammatory in several disease models . Besides, cordycepin possesses anticancer activities, such as anti-proliferation, anti-migration, apoptosis induction, and autophagy promotion.

Cordycepin, extracted from Cordyceps ssp., has been revealed as a strong anticancer agent through several ways; however, the mechanism, by which cordycepin counteracts brain cancers, is still poorly understood. In a recent study, the underlying mechanisms of cordycepin against human brain cancer cells were explored. SH-SY5Y and U251 cells were being a model to represent human neuroblastoma and glioblastoma, respectively. Here, it was found that cordycepin inhibited cell growth, and induced apoptosis in a dose-dependent manner in both SH-SY5Y and U-251 cell lines. The expression of pro-apoptotic genes, including P53BAXCaspase-3, and Caspase-9, were upregulated, whereas the expression of anti-apoptotic gene, BCL-2, was suppressed. Besides, cordycepin induced the generation of reactive oxygen species (ROS) along with the suppression of antioxidant genes, including GPXSOD, and Catalase. Importantly, cordycepin was shown to involve in the activation of autophagy, which was evidenced by the increment of LC3I/II. The combination of cordycepin with chloroquine, an autophagy inhibitor, further inhibited the growth, and enhanced the death of brain cancer cells. Altogether, this finding suggested that cordycepin induced apoptosis of human brain cancer cells through mitochondrial-mediated intrinsic pathway and the modulation of autophagy. 

This study reflects the importance of autophagy in chemosensitizing of human brain cancer cells to anticancer agents, and, in the near future, cordycepin could be implemented in a combination with conventional anticancer drugs to augment the treatment efficacy against brain cancers .

In conclusion, cordycepin could effectively inhibit the proliferation and induce apoptotic cell death of human brain cancer cells through the generation of reactive oxygen species and modulation of autophagy. The control of autophagy activity within cells by small molecules might be an alternative approach for a better treatment of human brain cancers. Importantly, this finding revealed the mechanisms of action of cordycepin, which is a foundation to study other relevant mechanistic insights into the mysterious potential of cordycepin. Future studies should focus on the enhancement of cordycepin absorption and bioavailability, and targeted-tissue delivery strategies using nanoparticles.!

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