Adenosine A2A receptor agonists and PDE inhibitors: a synergistic multitarget mechanism discovered through systematic combination screening in B-cell malignancies.
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.
Rickles
Richard J
RJ
CombinatoRx Inc., 245 1st St., Cambridge, MA 02142, USA. rrickles@combinatorx.com
Pierce
Laura T
LT
Giordano
Thomas P
TP
Tam
Winnie F
WF
McMillin
Douglas W
DW
Delmore
Jake
J
Laubach
Jacob P
JP
Borisy
Alexis A
AA
Richardson
Paul G
PG
Lee
Margaret S
MS
D058908:Adenosine A2 Receptor Agonists; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001402:B-Lymphocytes / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004357:Drug Synergism; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000473:pathology; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage* / Q000302:isolation & purification / Q000494:pharmacology; D054928:Validation Studies as Topic
D058908:Adenosine A2 Receptor Agonists; D005938:Glucocorticoids; D010726:Phosphodiesterase Inhibitors; D003907:Dexamethasone