Cordycepin (3'-Deoxyadenosine) Suppresses Heat Shock Protein 90 Function and Targets Tumor Growth in an Adenosine Deaminase-Dependent Manner

Area of Science:

• Metabolic alterations in cancer
• Adenosine metabolism and cancer pathways

Background:

• Metabolic reprogramming is a key driver of cancer development.
• Cordycepin (3'-deoxyadenosine) is an adenosine analog with known anti-cancer properties.
• Its efficacy and mechanisms in various malignancies remain largely unexplored.

Purpose of the Study:

• To investigate the anti-cancer effects of cordycepin in hard-to-treat malignancies.
• To elucidate the role of adenosine deaminase (ADA) in cordycepin's efficacy.
• To identify novel mechanisms of cordycepin action.

Main Methods:

• Testing cordycepin's effects on uveal melanoma, retinoblastoma, atypical teratoid rhabdoid tumors, and diffuse midline gliomas.
• Assessing the impact of adenosine deaminase (ADA) expression levels on tumor response.
• Utilizing siRNA and pharmacologic inhibitors to modulate ADA activity.
• Investigating cordycepin's interaction with Hsp90 and its client proteins.

Main Results:

• Cordycepin demonstrated growth inhibition and apoptosis induction in multiple rare cancer types.
• Efficacy of cordycepin was significantly correlated with low adenosine deaminase (ADA) expression or activity.
• Inhibition of ADA sensitized tumors with higher ADA levels to cordycepin, enhancing apoptosis and reducing cell migration and clonogenic capacity.
• Cordycepin was found to compete with ATP for binding to Hsp90, disrupting oncogenic client protein processing.

Conclusions:

• Cordycepin exhibits broad anti-cancer activity against challenging malignancies.
• Adenosine deaminase (ADA) is a predictive biomarker for cordycepin response and a potential therapeutic target for combination therapy.
• Cordycepin's novel mechanism involves Hsp90 inhibition via ATP competition, impacting oncogenic pathways.