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

Ikeda, Ryuji; Furukawa, Tatsuhiko; Kitazono, Masaki; Ishitsuka, Kenji; Okumura, Hiroshi; Tani, Akira; Sumizawa, Tomoyuki; Haraguchi, Masanobu; Komatsu, Masaharu; Uchimiya, Hiroshi; Ren, Xiao‐Qin; Motoya, Toshiro; Yamada, Katsushi; Akiyama, Shin–ichi

doi:10.1006/bbrc.2002.6432

Cited by 59 publications

(49 citation statements)

References 27 publications

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“…Fas-induced apoptosis in KB cells, transfected with TPase (KB/TPase) (31), and cisplatin-induced apoptosis in Jurkat/TPase cells (32) does not seem to require TPase enzymatic activity. In contrast, the enzymatic activity of TPase is required for apoptosis induced by hypoxia in KB/TPase (33) and HL60 cells (34).…”

Section: Discussionmentioning

confidence: 97%

The Nucleoside Derivative 5′-O-Trityl-inosine (KIN59) Suppresses Thymidine Phosphorylase-triggered Angiogenesis via a Noncompetitive Mechanism of Action

Liekens

Hernández

Ribatti

et al. 2004

Journal of Biological Chemistry

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Thymidine phosphorylase (TPase) catalyzes the reversible phosphorolysis of pyrimidine deoxynucleosides to 2-deoxy-D-ribose-1-phosphate and their respective pyrimidine bases. The enzymatic activity of TPase was found to be essential for its angiogenesis-stimulating properties. All of the previously described TPase inhibitors are either pyrimidine analogues that interact with the nucleosidebinding site of the enzyme or modified purine derivatives that mimic the pyrimidine structure and either compete with thymidine or act as a multisubstrate (competitive) inhibitor. We now describe the inhibitory activity of the purine riboside derivative KIN59 (5 -O-tritylinosine) against human and bacterial recombinant TPase and TPase-induced angiogenesis. In contrast to previously described TPase inhibitors, KIN59 does not compete with the pyrimidine nucleoside or the phosphate-binding site of the enzyme but noncompetitively inhibits TPase when thymidine or phosphate is used as the variable substrate. In addition, KIN59 was far more active than other TPase inhibitors, previously tested by us, against TPase-induced angiogenesis in the chorioallantoic membrane assay. The observed anti-angiogenic effect of KIN59 was not accompanied by inflammation or any visible toxicity. Inosine did not inhibit the enzymatic or angiogenic activity of the enzyme, indicating that the 5 -O-trityl group in KIN59 is essential for the observed effects. In contrast with current concepts, our data indicate that the angiogenic activity of TPase is not solely directed through its functional nucleoside and phosphate-binding sites. Other regulatory (allosteric) site(s) in TPase may play an important role in the mechanism of TPase-triggered angiogenesis stimulation and apoptosis inhibition. Identification of these site(s) is important to obtain a better insight into the molecular role of TPase in the progression of cancer and angiogenic diseases.Angiogenesis is the process by which new blood vessels arise from pre-existing vessels (1). It is essential during embryogenesis for the formation of a vascular plexus, which ensures an adequate blood supply to all developing tissues. In adults, neovascularization is limited to wound healing and the female reproductive cycle. During these processes, angiogenesis is tightly regulated. Unregulated angiogenesis may lead to the progression of several inflammatory diseases and is an essential component of solid tumor growth and metastasis. The formation of new blood vessels requires several sequential steps, which are regulated by a number of angiogenic factors, including chemokines, growth factors, integrins, and enzymes, such as proteases and thymidine phosphorylase (TPase) 1 (1).TPase is an enzyme that catalyzes the reversible phosphorolysis of pyrimidine 2Ј-deoxynucleosides to 2-deoxyribose 1-phosphate and their respective pyrimidine bases. TPase also recognizes several nucleoside analogues that are being used clinically as antiviral

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Section: Discussionmentioning

confidence: 97%

The Nucleoside Derivative 5′-O-Trityl-inosine (KIN59) Suppresses Thymidine Phosphorylase-triggered Angiogenesis via a Noncompetitive Mechanism of Action

Liekens

Hernández

Ribatti

et al. 2004

Journal of Biological Chemistry

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“…We show that in the presence of hypoxia, TP activity further increases the induction of cellular HIF-1a. In contrast, others have shown that the enzymatic product of thymidine phosphorylase's action on thymidine, 2-deoxy-D-ribose, attenuates the hypoxic induction of HIF-1a in the leukaemic cell line HL-60 (Ikeda et al, 2002). It is therefore possible that different tumour cell lines may demonstrate considerable variation when studying the effects of TP activity upon HIF-1a induction.…”

Section: Discussionmentioning

confidence: 98%

“…It is therefore possible that different tumour cell lines may demonstrate considerable variation when studying the effects of TP activity upon HIF-1a induction. It has been known for several years that 2-deoxy-D-ribose reduces hypoxia-induced apoptosis in the cell lines KB-3-1 and HL-60 (Kitazono et al, 1998) (Ikeda et al, 2002). It would therefore be of future interest to determine whether TP activity promotes or represses hypoxia-induced apoptosis in our bladder carcinoma cell line.…”

Section: Discussionmentioning

confidence: 99%

Cooperative stimulation of vascular endothelial growth factor expression by hypoxia and reactive oxygen species: the effect of targeting vascular endothelial growth factor and oxidative stress in an orthotopic xenograft model of bladder carcinoma

et al. 2005

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Elevated thymidine phosphorylase has been shown to correlate with increased angiogenesis and poor prognosis in many cancers including transitional cell carcinoma of the bladder. In vitro studies have demonstrated that thymidine phosphorylase activity causes cellular oxidative stress and increases secretion of vascular endothelial growth factor. In this study, we show that thymidine phosphorylase activity also augments levels of the hypoxia-inducible factor-1a during in vitro hypoxia, and that thymidine phosphorylase activity and hypoxia act in concert to increase vascular endothelial growth factor (VEGF) secretion. We also demonstrate that thymidine phosphorylase overexpression confers tumorigenicity on an orthotopically implanted transitional cell carcinoma cell line. Administration of the antioxidant N-acetylcysteine together with a blocking anti-VEGF antibody abrogates the increase in tumorigenicity. Our results support the increased efficacy of combination approaches to antiangiogenic therapy.

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“…28) Furthermore, both TP and D-dRib inhibited down-regulation of the pro-apoptotic bcl-2 and bcl-X L , mitochondrial cytochrome c release and caspase 3 activation that were induced in HL60 cells under hypoxic conditions. 29) These data indicate that TP confers resistance to apoptosis induced by hypoxia, and that the enzymatic degradation of thymidine by TP is required for the inhibition of hypoxia-induced apoptosis. The finding that TP can confer resistance to apoptosis, in addition to its angiogenic activity, may explain why breast carcinoma cells that overexpress TP show enhanced growth, but no increased vessel density in vivo.…”

Section: Tp and D-drib Inhibit Hypoxia-induced Apoptosismentioning

confidence: 90%

The role of thymidine phosphorylase, an angiogenic enzyme, in tumor progression

et al. 2004

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

Cited by 59 publications

References 27 publications

The Nucleoside Derivative 5′-O-Trityl-inosine (KIN59) Suppresses Thymidine Phosphorylase-triggered Angiogenesis via a Noncompetitive Mechanism of Action

The Nucleoside Derivative 5′-O-Trityl-inosine (KIN59) Suppresses Thymidine Phosphorylase-triggered Angiogenesis via a Noncompetitive Mechanism of Action

Cooperative stimulation of vascular endothelial growth factor expression by hypoxia and reactive oxygen species: the effect of targeting vascular endothelial growth factor and oxidative stress in an orthotopic xenograft model of bladder carcinoma

The role of thymidine phosphorylase, an angiogenic enzyme, in tumor progression

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