Bastadin 6, a spongean brominated tyrosine derivative, inhibits tumor angiogenesis by inducing selective apoptosis to endothelial cells

Bastadin 6, a macrocyclic tetramer of a brominated tyrosine derivative, was isolated from a marine sponge and its anti-angiogenic activity was evaluated. Bastadin 6 was found to inhibit vascular endothelial growth factor (VEGF)- or basic fibroblast growth factor (bFGF)-dependent proliferation (IC50=0.052 μmol/l) of human umbilical vein endothelial cells (HUVECs) 20- to 100-fold selectively in comparison with normal fibroblast (3Y1) or several tumor cells (KB3-1, K562 and Neuro2A). Bastadin 6 also inhibited VEGF- or bFGF-induced tubular formation (0.1 μmol/l, 6 h treatment) and VEGF-induced migration (1 μmol/l, 4 h treatment) of HUVECs. Moreover, bastadin 6 almost completely blocked VEGF- or bFGF-induced in vivo neovascularization in the mice corneal assay and suppressed growth of s.c. inoculated A431 solid tumor in nude mice (100 mg/kg, i.p.). Bastadin 6 induced cell death of HUVECs with an apoptotic phenotype, whereas it showed no effect on the VEGF-induced auto-phosphorylation of VEGF receptors Flt-1 and KDR/Flk-1. These results suggest that the anti-angiogenic effect of bastadin 6 is closely related to selective induction activity of apoptosis against endothelial cells.

[1]  Yukihiro Asami,et al.  RK-805, an endothelial-cell-growth inhibitor produced by Neosartorya sp., and a docking model with methionine aminopeptidase-2 , 2004 .

[2]  P. O'dwyer,et al.  Monoclonal antibodies in the treatment of colorectal cancer. , 2004, European journal of cancer.

[3]  S. Kihara,et al.  Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Ricky T. Tong,et al.  Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer , 2004, Nature Medicine.

[5]  E. Anaissie,et al.  Phase II Study of SU5416, a Small Molecule Vascular Endothelial Growth Factor Tyrosine Kinase Receptor Inhibitor, in Patients with Refractory Multiple Myeloma , 2004, Clinical Cancer Research.

[6]  Philip Hahnfeldt,et al.  Combined therapy with direct and indirect angiogenesis inhibition results in enhanced antiangiogenic and antitumor effects. , 2003, Cancer research.

[7]  F. Rastinejad,et al.  Pharmacological characterization of CP-547,632, a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for cancer therapy. , 2003, Cancer research.

[8]  R. Gilbert,et al.  STI-571 inhibits in vitro angiogenesis. , 2003, Biochemical and biophysical research communications.

[9]  J. Mier,et al.  Canstatin Inhibits Akt Activation and Induces Fas-dependent Apoptosis in Endothelial Cells* , 2003, Journal of Biological Chemistry.

[10]  N. Chandel,et al.  Angiostatin4.5-mediated Apoptosis of Vascular Endothelial Cells , 2003 .

[11]  N. Chandel,et al.  Angiostatin(4.5)-mediated apoptosis of vascular endothelial cells. , 2003, Cancer research.

[12]  B. Curry,et al.  ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. , 2002, Cancer research.

[13]  He-long Zhang,et al.  Activity of a new vascular targeting agent, ZD6126, in pulmonary metastases by human lung adenocarcinoma in nude mice. , 2002, Cancer research.

[14]  T. Furukawa,et al.  Lembehsterols A and B, novel sulfated sterols inhibiting thymidine phosphorylase, from the marine sponge Petrosia strongylata. , 2002, Chemical & pharmaceutical bulletin.

[15]  M. Kuwano,et al.  ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. , 2002, Cancer research.

[16]  K. Weinberg,et al.  αv‐Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin , 2002, International journal of cancer.

[17]  D. Gingras,et al.  The antiangiogenic agent neovastat (AE-941) inhibits vascular endothelial growth factor-mediated biological effects. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  J. Fargnoli,et al.  Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291. , 2001, Cancer research.

[19]  A. Pries,et al.  Expression of ryanodine receptor type 3 and TRP channels in endothelial cells: comparison of in situ and cultured human endothelial cells. , 2001, Cardiovascular research.

[20]  T. L. Moser,et al.  Endothelial cell surface F1-FO ATP synthase is active in ATP synthesis and is inhibited by angiostatin , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. Hitt,et al.  Combined Treatment of a Murine Breast Cancer Model with Type 5 Adenovirus Vectors Expressing Murine Angiostatin and IL-12: A Role for Combined Anti-Angiogenesis and Immunotherapy1 , 2001, The Journal of Immunology.

[22]  S. Pizzo,et al.  内皮細胞表面F1‐F0ATPシンターゼはATP合成に働き、アンギオスタチンにより阻害される , 2001 .

[23]  Cherrington,et al.  SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. , 2000, Cancer research.

[24]  Eric C. Griffith,et al.  Cell cycle inhibition by the anti-angiogenic agent TNP-470 is mediated by p53 and p21WAF1/CIP1. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[25]  R. Kalluri,et al.  Canstatin, a Novel Matrix-derived Inhibitor of Angiogenesis and Tumor Growth* , 2000, The Journal of Biological Chemistry.

[26]  O. Volpert,et al.  Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1 , 2000, Nature Medicine.

[27]  T. Molinski,et al.  Bastadin 10 Stabilizes the Open Conformation of the Ryanodine-sensitive Ca2+ Channel in an FKBP12-dependent Manner* , 1999, The Journal of Biological Chemistry.

[28]  V. Sukhatme,et al.  Endostatin Induces Endothelial Cell Apoptosis* , 1999, The Journal of Biological Chemistry.

[29]  A. Ullrich,et al.  SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. , 1999, Cancer research.

[30]  Eric C. Griffith,et al.  Molecular recognition of angiogenesis inhibitors fumagillin and ovalicin by methionine aminopeptidase 2. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Leonard,et al.  Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. , 1997, Cancer research.

[32]  M. Shibuya,et al.  The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-γ pathway and partially induces mitotic signals in NIH3T3 fibroblasts , 1997, Oncogene.

[33]  H. Krutzsch,et al.  Thrombospondin 1 and type I repeat peptides of thrombospondin 1 specifically induce apoptosis of endothelial cells. , 1997, Cancer research.

[34]  T. Molinski,et al.  Bastadins relate ryanodine-sensitive and -insensitive Ca2+ efflux pathways in skeletal SR and BC3H1 cells. , 1997, The American journal of physiology.

[35]  M. Shibuya,et al.  A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. , 1995, Oncogene.

[36]  T. Molinski,et al.  Novel modulators of skeletal muscle FKBP12/calcium channel complex from Ianthella basta. Role of FKBP12 in channel gating. , 1994, The Journal of biological chemistry.

[37]  D. Ingber,et al.  Cytostatic inhibition of endothelial cell growth by the angiogenesis inhibitor TNP-470 (AGM-1470). , 1994, British Journal of Cancer.

[38]  M. Mack,et al.  Novel Modulators of Skeletal Muscle FKBPWCalcium Channel Complex from Ianthella basta , 1994 .

[39]  A. Yoshimura,et al.  Angiogenic factor , 1992, Nature.

[40]  J. Blount,et al.  Brominated tyrosine-derived metabolites from the sponge Ianthella basta , 1980 .