Molecular Basis for the Inhibition of Hypoxia-Induced Apoptosis by 2-Deoxy- d-ribose

Abstract

An angiogenic factor, platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP), stimulates the chemotaxis of endothelial cells and confers resistance to apoptosis induced by hypoxia. 2-Deoxy- d-ribose, a degradation product of thymidine generated by TP enzymatic activity partially prevented hypoxia-induced apoptosis. 2-Deoxy- d-ribose inhibits a number of components of the caspase-mediated hypoxia-induced apoptotic pathway. It inhibits hypoxia-induced caspase 3 activation, mitochondrial cytochrome c release, downregulation of Bcl-2 and Bcl-x L, upregulation of hypoxia-inducible factor (HIF)-1α, and loss of mitochondrial transmembrane potential in human leukemia HL-60 cell line. These findings suggest a molecular mechanism by which 2-deoxy- d-ribose confers the resistance to apoptosis. Thus 2-deoxy- d-ribose-modulated suppression of HIF-1α expression could prevent the hypoxia-induced decrease of the anti-apoptotic Bcl-2 and Bcl-x L on the mitochondria. 2-Deoxy- l-ribose and its analogs may enhance apoptosis and suppress the growth of tumors by competitively inhibiting the activities of 2-deoxy- d-ribose and thus these analogs show promise for anti-tumor therapy.