Multifaceted actions of 8-amino-adenosine kill BCR–ABL positive cells

Abstract

Survival of chronic myelogenous leukemia (CML) cells is dependent on BCR–ABL kinase, the activity of which is contingent on the level of BCR–ABL protein and the availability of adenosine triphosphate (ATP). We hypothesized that 8-amino-adenosine (8-amino-Ado)-mediated reduction in cellular ATP level and inhibition of mRNA synthesis leading to a decrease in protein level would result in a multifaceted targeting of BCR–ABL. Using K562 cells, we demonstrated that there was a dose- and time-dependent increase in 8-amino-ATP accompanied by a > 95% decline in the endogenous ATP pool. In parallel, 8-amino-Ado inhibited RNA synthesis and resulted in a depletion of BCR–ABL transcript. Consistent with this, BCR–ABL and ABL protein levels were also decreased. These effects were associated with the initiation of cell death as visualized by poly(ADP-ribose) polymerase (PARP) cleavage, decreased clonogenicity and greater than additive interaction with imatinib. In imatinib-sensitive and -resistant KBM5 cells, 8-amino-Ado treatment augmented the imatinib effect on growth inhibition.

Keywords::

• ATP analog
• BCR–ABL
• apoptosis
• transcription
• 8-amino-adenosine

Acknowledgements

This work was supported in part by a Lymphoma SPORE (CA136411) grant from the National Cancer Institute, Department of Health and Human Services.

Potential conflict of interest:

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