Vitamin E analogues inhibit angiogenesis by selective induction of apoptosis in proliferating endothelial cells: the role of oxidative stress.
"Mitocans" from the vitamin E group of selective anticancer drugs, alpha-tocopheryl succinate (alpha-TOS) and its ether analogue alpha-TEA, triggered apoptosis in proliferating but not arrested endothelial cells. Angiogenic endothelial cells exposed to the vitamin E analogues, unlike their arrested counterparts, readily accumulated reactive oxygen species (ROS) by interfering with the mitochondrial redox chain and activating the intrinsic apoptotic pathway. The vitamin E analogues inhibited angiogenesis in vitro as assessed using the "wound-healing" and "tube-forming" models. Endothelial cells deficient in mitochondrial DNA (mtDNA) were resistant to the vitamin E analogues, both in ROS accumulation and apoptosis induction, maintaining their angiogenic potential. alpha-TOS inhibited angiogenesis in a mouse cancer model, as documented by ultrasound imaging. We conclude that vitamin E analogues selectively kill angiogenic endothelial cells, suppressing tumor growth, which has intriguing clinical implications.
Dong
Lan-Feng
LF
Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Queensland, Australia.
Swettenham
Emma
E
Eliasson
Johanna
J
Wang
Xiu-Fang
XF
Gold
Mikhal
M
Medunic
Yasmine
Y
Stantic
Marina
M
Low
Pauline
P
Prochazka
Lubomir
L
Witting
Paul K
PK
Turanek
Jaroslav
J
Akporiaye
Emmanuel T
ET
Ralph
Stephen J
SJ
Neuzil
Jiri
J
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000235:genetics; D004351:Drug Resistance; D004730:Endothelium, Vascular; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D014810:Vitamin E