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

Abstract

Simple SummaryOur study contributes to understanding the therapeutic effects of cordycepin in cancer. First, we find that the anticancer effects of cordycepin alone are only seen in tumor cell lines with low ADA expression or activity. This was true in multiple tumor types and may be applied as a predictive biomarker for the future treatment of patients. Second, we show that inhibition of ADA enhances cordycepin’s anticancer effects by blocking its conversion to 3′-deoxyinosine in uveal melanoma and several other tumors. This raises the possibility of clinical combination treatments with cordycepin and ADA inhibitors, and our data suggest that much lower doses of cordycepin are possible in this context. Third, we identified a new mechanism of action for cordycepin: inhibiting the function of a protein known as Hsp90.Alterations in metabolism and energy production are increasingly being recognized as important drivers of neoplasia, raising the possibility that metabolic analogs could disrupt oncogenic pathways. 3′-deoxyadenosine, also known as cordycepin, is an adenosine analog that inhibits the growth of several types of cancer. However, the effects of cordycepin have only been examined in a limited number of tumor types, and its mechanism of action is poorly understood. We found that cordycepin slows the growth and promotes apoptosis in uveal melanoma, as well as a range of other hard-to-treat malignancies, including retinoblastoma, atypical teratoid rhabdoid tumors, and diffuse midline gliomas. Interestingly, these effects were dependent on low adenosine deaminase (ADA) expression or activity. Inhibition of ADA using either siRNA or pharmacologic approaches sensitized tumors with higher ADA to cordycepin in vitro and in vivo, with increased apoptosis, reduced clonogenic capacity, and slower migration of neoplastic cells. Our studies suggest that ADA is both a biomarker predicting response to cordycepin and a target for combination therapy. We also describe a novel mechanism of action for cordycepin: competition with adenosine triphosphate (ATP) in binding to Hsp90, resulting in impaired processing of oncogenic Hsp90 client proteins.