8-Aminoadenosine inhibits Akt/mTOR and Erk signaling in mantle cell lymphoma.

Abstract

8-Aminoadenosine (8-NH(2)-Ado), a ribosyl nucleoside analog, in preclinical models of multiple myeloma inhibits phosphorylation of proteins in multiple growth and survival pathways, including Akt. Given that Akt controls the activity of mammalian target of rapamycin (mTOR), we hypothesized that 8-NH(2)-Ado would be active in mantle cell lymphoma (MCL), a hematological malignancy clinically responsive to mTOR inhibitors. In the current study, the preclinical efficacy of 8-NH(2)-Ado and its resulting effects on Akt/mTOR and extracellular-signal-regulated kinase signaling were evaluated using 4 MCL cell lines, primary MCL cells, and normal lymphocytes from healthy donors. For all MCL cell lines, 8-NH(2)-Ado inhibited growth and promoted cell death as shown by reduction of thymidine incorporation, loss of mitochondrial membrane potential, and poly (adenosine diphosphate-ribose) polymerase cleavage. The efficacy of 8-NH(2)-Ado was highly associated with intracellular accumulation of 8-NH(2)-adenosine triphosphate (ATP) and loss of endogenous ATP. Formation of 8-NH(2)-ATP was also associated with inhibition of transcription and translation accompanied by loss of phosphorylated (p-)Akt, p-mTOR, p-Erk1/2, p-phosphoprotein (p)38, p-S6, and p-4E-binding protein 1. While normal lymphocytes accumulated 8-NH(2)-ATP but maintained their viability with 8-NH(2)-Ado treatment, primary lymphoma cells accumulated higher concentrations of 8-NH(2)-ATP, had increased loss of ATP, and underwent apoptosis. We conclude that 8-NH(2)-Ado is efficacious in preclinical models of MCL and inhibits signaling of Akt/mTOR and Erk pathways.

• Authors: Jennifer B Dennison, Mala Shanmugam, Mary L Ayres, Jun Qian, Nancy L Krett, L Jeffrey Medeiros, Sattva S Neelapu, Steven T Rosen, Varsha Gandhi
• Journal: Blood (Blood) Vol. 116 Issue 25 Pg. 5622-30 (Dec 16 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20844237 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• 8-aminoadenosine
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Extracellular Signal-Regulated MAP Kinases
• Adenosine

Topics

• Adenosine (analogs & derivatives, pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Flow Cytometry
• Humans
• Lymphoma, Mantle-Cell (drug therapy, metabolism, pathology)
• Phosphorylation (drug effects)
• Protein Biosynthesis (drug effects)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Transcription, Genetic (drug effects)
• Tumor Cells, Cultured