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¹ Robert H. Lurie Comprehensive Cancer Center and ² Division of Hematology Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois and ³ Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Nancy L. Krett, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 East Chicago Avenue, Olson 8340, Chicago, IL 60611. Phone: 312-908-5919; Fax: 312-908-1372. E-mail: n-krett{at}northwestern.edu

Multiple myeloma is a slowly proliferating B-cell malignancy that accumulates apoptosis-resistant and replication-quiescent cell populations, posing a challenge for current chemotherapeutics that target rapidly replicating cells. Multiple myeloma remains an incurable disease in need of new therapeutic approaches. The purine nucleoside analogue, 8-amino-adenosine (8-NH₂-Ado), exhibits potent activity in preclinical studies, inducing apoptosis in several multiple myeloma cell lines. This cytotoxic effect requires phosphorylation of 8-NH₂-Ado to its triphosphate form, 8-amino-ATP, and results in a concomitant loss of endogenous ATP levels. Here, we show the novel effect of 8-NH₂-Ado on the phosphorylation status of key cellular signaling molecules. Multiple myeloma cells treated with 8-NH₂-Ado exhibit a dramatic loss of phosphorylation of several important signaling proteins, including extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and Akt kinase. Cells depleted of ATP independent of 8-NH₂-Ado do not exhibit the same decrease in phosphorylation of vital cellular proteins. Therefore, the significant shifts in endogenous ATP pools caused by 8-NH₂-Ado treatment cannot account for the changes in phosphorylation levels. Instead, 8-NH₂-Ado may influence the activity of select regulatory protein kinases and/or phosphatases, with preliminary data suggesting that protein phophatase 2A activity is affected by 8-NH₂-Ado. The distinctive effect of 8-NH₂-Ado on the phosphorylation status of cellular proteins is a novel phenomenon for a nucleoside analogue drug and is unique to 8-NH₂-Ado among this class of drugs. The kinetics of 8-NH₂-Ado-mediated changes in phosphorylation levels of critical prosurvival and apoptosis-regulating proteins suggests that the modulation of these proteins by dephosphorylation at early time points may be an important mechanistic step in 8-NH₂-Ado-induced apoptosis.

Key Words: nucleoside analogue • signaling • phosphorylation • multiple myeloma • therapy

Grant support: National Cancer Institute, Department of Health grant CA85915 and NIH/National Cancer Institute training grant T32CA09560 (K. Ghias).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org).

Received 11/12/04; revised 1/ 6/05; accepted 2/ 3/05.