8-Amino-adenosine induces loss of phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2, and Akt kinase: Role in induction of apoptosis in multiple myeloma

• Published in: Molecular cancer therapeutics Vol. 4; no. 4; pp. 569 - 577
• Main Authors: Ghias, Kulsoom, Ma, Chunguang, Gandhi, Varsha, Platanias, Leonidas C, Krett, Nancy L, Rosen, Steven T
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-04-2005
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Adenosine Triphosphate - chemistry; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Flow Cytometry; Humans; Immunoblotting; JNK Mitogen-Activated Protein Kinases - metabolism; Kinetics; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; multiple myeloma; Multiple Myeloma - pathology; nucleoside analogue; Nucleosides - chemistry; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Purines - chemistry; Signal Transduction; signaling; therapy; Time Factors
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-04-0303

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-NH 2 -Ado), exhibits potent activity in preclinical studies, inducing apoptosis in several multiple myeloma cell lines. This cytotoxic
effect requires phosphorylation of 8-NH 2 -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-NH 2 -Ado on the phosphorylation status of key cellular signaling molecules. Multiple myeloma cells treated with 8-NH 2 -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-NH 2 -Ado do not exhibit the same decrease in phosphorylation of vital cellular proteins. Therefore, the significant shifts in
endogenous ATP pools caused by 8-NH 2 -Ado treatment cannot account for the changes in phosphorylation levels. Instead, 8-NH 2 -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-NH 2 -Ado. The distinctive effect of 8-NH 2 -Ado on the phosphorylation status of cellular proteins is a novel phenomenon for a nucleoside analogue drug and is unique
to 8-NH 2 -Ado among this class of drugs. The kinetics of 8-NH 2 -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-NH 2 -Ado-induced apoptosis.