Molecular basis for the inhibition of hypoxia-induced apoptosis by 2-deoxy-D-ribose.

Ryuji Ikeda, Tatsuhiko Furukawa, Masaki Kitazono, Kenji Ishitsuka, Hiroshi Okumura, Ayako Tani, Tomoyuki Sumizawa, Misako Haraguchi, Masaharu Komatsu, Hiroshi Uchimiya, Xiao-Qin Ren, Toshiro Motoya, Katsushi Yamada, Shin-ichi Akiyama

Index: Biochem. Biophys. Res. Commun. 291(4) , 806-12, (2002)

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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)-1 alpha, 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-1 alpha 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.