Adenosine and hypoxia stimulate proliferation and migration of endothelial cells

Meininger, Cynthia J.; Schelling, Margaret E.; Granger, Harris J.

doi:10.1152/ajpheart.1988.255.3.h554

Cited by 111 publications

(91 citation statements)

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“…Next, the proliferation of BAECs was determined by [ 3 H]-methylthymidine incorporation assay. The DNA synthesis of cells was increased under hypoxia as reported previously, 31 but the FK228 (10 ng/ml) effectively suppressed the hypoxia-stimulated DNA synthesis (Fig. 2a).…”

Section: Fk228 Showed Potent Antiangiogenic Activities In Vitrosupporting

confidence: 86%

Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis

Kwon

Kim

et al. 2001

Intl Journal of Cancer

166

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FK228 (formerly FR901228) was recently isolated fromChromobacterium violaceum as a potent antitumor agent and its biologic target protein was identified as histone deacetylase (HDAC). Because of its unique chemical structure (i.e., bicyclic depsipeptide) and activity profile in the National Cancer Institute's developmental therapeutics program, FK228 is currently in a phase I clinical trial for cancer therapy. In the present study, we investigated the antiangiogenic activity of FK228 in vivo and in vitro. FK228 potently blocked the hypoxia-stimulated proliferation, invasion, migration, adhesion and tube formation of bovine aortic endothelial cells at the same concentration at which the agent inhibited the HDAC activity of cells. In addition, FK228 inhibited the neovascularization of chick embryo and that of adult mice in the Matrigel plug assay. Interestingly, the expression of angiogenic-stimulating factors such as vascular endothelial growth factor or kinase insert domain receptor were suppressed by FK228, whereas that of angiogenic-inhibiting factors such as von Hippel Lindau and neurofibromin2 were induced, suggesting that a gene-transcription effect was involved in the inhibition of angiogenesis by FK228. These results indicate that FK228 is a novel antiangiogenic agent and may suppress tumor expansion, at least in part, by the inhibition of neovascularization. © 2002 Wiley-Liss, Inc. Key words: FK228; angiogenesis; histone deacetylases; antitumor agentAngiogenesis is the multistep process of new blood vessel formation by endothelial cells. The process is controlled by oppositely regulating factors that induce or suppress endothelial cell growth. The corruption of this balance is directly related with pathologic diseases such as outgrowth and spreading of cancer cells, diabetic retinopathy, rheumatoid and ischemia. 1 Extensive studies have been conducted to elucidate the mechanism and to develop therapeutic methods. Antiangiogenic agents have gathered special attention because they could be new anticancer therapeutic agents with different mode of actions from the anticancer drugs used currently. To date, several agents have been developed for this purpose. These include angiostatin, 2 endostatin 3 and canstatin 4 as endogenous peptide inhibitors and TNP-470, 5 eponemycin, 6 radicicol 7 and depudecin 8 as low molecular weight compounds from microbial metabolites and thalidomide, 9 marimastat 10 and SU6668 11 as synthetic inhibitors. Most of these agents inhibit the activity of metalloproteinases or the kinase activity of the vascular endothelial growth factor (VEGF) receptor, Flk/KDR, which are thought to be crucial and specific for the angiogenesis.Meanwhile, hypoxia is considered to be one of the key factors to trigger angiogenesis by the induction of angiogenic factors such as VEGF and hypoxia-inducible factor-1␣ (HIF-1␣). 12,13 Adaptation to hypoxia involves appropriate alterations in the expression of a number of angiogenesis-responsive genes. 14 The covalent acetylation of histones is known to play sig...

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Section: Fk228 Showed Potent Antiangiogenic Activities In Vitrosupporting

confidence: 86%

Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis

Kwon

Kim

et al. 2001

Intl Journal of Cancer

166

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“…That the enzyme activity is required for angiogenic activity was shown with three active site mutants that maintained their secondary structure, as determined by their capacity to dimerize, but had reduced TP activity. The mutants did not exhibit angiogenic activity in the rat sponge model when assayed at the (25) and to be angiogenic in vivo (26). TP hydrolyzes thymidine to 2'-deoxy-D-ribose 1-phosphate and thymine.…”

Section: Discussionmentioning

confidence: 95%

Thymidine phosphorylase is angiogenic and promotes tumor growth.

Moghaddam¹,

Zhang²,

Fan³

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

344

201

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Platelet-derived endothelial cell growth factor was previously identified as the sole angiogenic activity present in platelets; it is now known to be thymidine phosphorylase (TP). Intense interest has recently centered on the angiogenic process, largely as a result of the realization that disregulated blood vessel growth plays a critical role in several disease states, including (inter alia) cancer (tumor angiogenesis), diabetic retinopathy, psoriasis, rheumatoid arthritis, and hyperproliferation of the vasa vasorum in atherosclerosis (1). Platelet-derived endothelial cell growth factor was described as a mitogenic and angiogenic factor present in platelets (2).Platelet-derived endothelial cell growth factor is now known to be thymidine phosphorylase (TP) (3) and the effects of TP on cellular uptake of [methyl-3H]thymidine when it is added exogenously to cells arise from its effect on the availability of thymidine in the extracellular culture medium (4-6). Several years prior to the isolation of the so-called plateletderived endothelial growth factor and demonstration of its angiogenic activity, TP had been identified as an enzyme whose level was significantly elevated in the plasma of cancer patients relative to that in healthy volunteers (7) and in the plasma of xenografted mice relative to that of controls (8) and expressed at a high level in tumors (9, 10). We have found (11) that expression of TP shows a strong correlation with ovarian malignancy and ovarian tumor blood flow.We report here that TP is angiogenic in the rat sponge model (12) and in a freeze-injured skin graft model (13). Expression of TP strongly correlated with malignancy in breast tumors, and while expression of TP had no effect on breast carcinoma cell growth in vitro, it greatly enhanced tumor growth in vivo. MATERIALS AND METHODSCell Isolation and Culture. Bovine aortic endothelial cells were isolated as described (14) and maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% (vol/vol) fetal calf serum. Low-passage MCF-7 cells (passage 53) were a gift from Marc Lippman (Georgetown University, Washington, DC).Antibodies to TP. Rabbit anti-TP antisera and mouse anti-TP monoclonal antibodies were raised against recombinant TP expressed in Escherichia coli (4).Site-Directed Mutagenesis and Protein Expression. Three site-directed mutants of TP were constructed by a two-step PCR (15). Recombinant proteins were expressed in E. coli using the expression vector pET-14b (ams Biotechnology, Witney, U.K.) and purified by metal chelate affinity chromatography. By gel filtration, recombinant TP was dimeric with a molecular mass of 100 kDa. Concentrations of pure TP were calculated by using a molecular mass of 100 kDa.Rat Sponge Angiogenesis Assay. Sterile circular polyether sponge discs with central cannula were implanted subcutaneously in male Wistar rats (180-200 g) after induction of neuroleptanalgesia by Hypnorm (12). Four sponges were used in each experimental group. Protein in 50 ,ul of PBS was injected daily into...

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“…Neovascularization is of relevance during inflammation, wound healing, and tumor growth and the study of these processes has resulted in the identification of a wide variety of angiogenesis inducers (3,4,15,19). The morphogenetic program of the neovascular response requires multiple steps, and an increase in blood flow and vasodilation of the parent venule before the emergence of the first capillary sprouts are important steps (6,32).…”

Section: Methodsmentioning

confidence: 99%

Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P.

Ziche¹,

Morbidelli²,

Masini³

et al. 1994

J. Clin. Invest.

796

507

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We evaluated the effects of nitric oxide (NO) generators and endogenous production of NO elicited by substance P (SP) in the angiogenesis process. Angiogenesis was monitored in the rabbit cornea in vivo and in vitro by measuring the growth and migration of endothelial cells isolated from coronary postcapillary venules. The angiogenesis promoted in the rabbit cornea by [Sari]-SP-sulfone, a stable and selective agonist for the tachykinin NK, receptor, and by prostaglandin El (PGE,), was potentiated by sodium nitroprusside (SNP). Conversely, the NO synthase inhibitor N"-nitro-Larginine methyl ester (L-NAME), given systemically, inhibited angiogenesis elicited by [Sar9]-SP-sulfone and by PGEj.Endothelial cells exposed to SNP exhibited an increase in thymidine incorporation and in total cell number. Exposure of the cells to NO generating drugs, such as SNP, isosorbide dinitrate, and glyceryl trinitrate, produced a dose-dependent increase in endothelial cell migration. Capillary endothelial cell proliferation and migration produced by SP were abolished by pretreatment with the NO synthase inhibitors, and L-NAME. Exposure of the cells to SP activated the calcium-dependent NO synthase. Angiogenesis and endothelial cell growth and migration induced by basic fibroblast growth factor were not affected by NO synthase inhibitors. These data indicate that NO production induced by vasoactive agents, such as SP, functions as an autocrine regulator of the microvascular events necessary for neovascularization and mediates angiogenesis. (J. Clin. Invest. 1994.94:2036-2044

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Adenosine and hypoxia stimulate proliferation and migration of endothelial cells

Cited by 111 publications

References 0 publications

Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis

Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis

Thymidine phosphorylase is angiogenic and promotes tumor growth.

Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P.

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