A peptide trivalent arsenical inhibits tumor angiogenesis by perturbing mitochondrial function in angiogenic endothelial cells.
Mitochondria are the powerhouse of the cell and their disruption leads to cell death. We have used a peptide trivalent arsenical, 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO), to inactivate the adenine nucleotide translocator (ANT) that exchanges matrix ATP for cytosolic ADP across the inner mitochondrial membrane and is the key component of the mitochondrial permeability transition pore (MPTP). GSAO triggered Ca(2+)-dependent MPTP opening by crosslinking Cys(160) and Cys(257) of ANT. GSAO treatment caused a concentration-dependent increase in superoxide levels, ATP depletion, mitochondrial depolarization, and apoptosis in proliferating, but not growth-quiescent, endothelial cells. Endothelial cell proliferation drives new blood vessel formation, or angiogenesis. GSAO inhibited angiogenesis in the chick chorioallantoic membrane and in solid tumors in mice. Consequently, GSAO inhibited tumor growth in mice with no apparent toxicity at efficacious doses.
Don
Anthony S
AS
Centre for Vascular Research, University of New South Wales and Department of Haematology, Prince of Wales Hospital, Sydney, Australia.
Kisker
Oliver
O
Dilda
Pierre
P
Donoghue
Neil
N
Zhao
Xueyun
X
Decollogne
Stephanie
S
Creighton
Belinda
B
Flynn
Evelyn
E
Folkman
Judah
J
Hogg
Philip J
PJ
D033741:Adenine Nucleotide Translocator 1 / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000166:cytology; D017209:Apoptosis; D001152:Arsenicals / Q000627:therapeutic use*; D001710:Biotin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D002455:Cell Division; D002470:Cell Survival; D002642:Chick Embryo; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004801:Eosine Yellowish-(YS) / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D007150:Immunohistochemistry; D007473:Ion Channels / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008956:Models, Chemical; D009389:Neovascularization, Pathologic; D010455:Peptides / Q000737:chemistry; D013997:Time Factors
D033741:Adenine Nucleotide Translocator 1; D020533:Angiogenesis Inhibitors; D001152:Arsenicals; D004791:Enzyme Inhibitors; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010455:Peptides; C029341:oxophenylarsine; D000244:Adenosine Diphosphate; D001710:Biotin; C033531:eosin maleimide; D000255:Adenosine Triphosphate; D002118:Calcium; D004801:Eosine Yellowish-(YS)