1. Adenosine A2A receptor agonists and PDE inhibitors: a synergistic multitarget mechanism discovered through systematic combination screening in B-cell malignancies.
- Author
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Rickles RJ, Pierce LT, Giordano TP 3rd, Tam WF, McMillin DW, Delmore J, Laubach JP, Borisy AA, Richardson PG, and Lee MS
- Subjects
- B-Lymphocytes pathology, Cell Line, Tumor, Cell Proliferation drug effects, Dexamethasone administration & dosage, Dexamethasone pharmacology, Drug Delivery Systems, Drug Synergism, Glucocorticoids administration & dosage, Glucocorticoids pharmacology, Hematologic Neoplasms metabolism, Hematologic Neoplasms pathology, High-Throughput Screening Assays methods, Humans, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse pathology, Multiple Myeloma drug therapy, Multiple Myeloma pathology, Phosphodiesterase Inhibitors isolation & purification, Phosphodiesterase Inhibitors pharmacology, Validation Studies as Topic, Adenosine A2 Receptor Agonists, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Drug Screening Assays, Antitumor methods, Hematologic Neoplasms drug therapy, Phosphodiesterase Inhibitors administration & dosage
- Abstract
Using a combination high-throughput screening technology, multiple classes of drugs and targeted agents were identified that synergize with dexamethasone (Dex) in multiple myeloma (MM) cells. Performing combination screening with these enhancers, we discovered an unexpected synergistic interaction between adenosine receptor agonists and phosphodiesterase (PDE) inhibitors that displays substantial activity in a panel of MM and diffuse large B-cell lymphoma (DLBCL) cell lines and tumor cells from MM patients. We have used selective adenosine receptor agonists, antagonists, and PDE inhibitors as well as small interfering RNAs targeting specific molecular isoforms of these proteins to dissect the molecular mechanism of this synergy. The adenosine A2A receptor and PDE2, 3, 4, and 7 are important for activity. Drug combinations induce cyclic AMP (cAMP) accumulation and up-regulate PDE4B. We also observe rigorous mathematical synergy in 3-way combinations containing A2A agonists, PDE inhibitors, and Dex at multiple concentrations and ratios. Taken together, these data suggest that A2A agonist/PDE inhibitor combinations may be attractive as an adjunctive to clinical glucocorticoid containing regiments for patients with MM or DLBCL and confer benefit in both glucocorticoid-sensitive and -resistant populations.
- Published
- 2010
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