A peptide conjugate of vitamin E succinate targets breast cancer cells with high ErbB2 expression.
Overexpression of erbB2 is associated with resistance to apoptosis. We explored whether high level of erbB2 expression by cancer cells allows their targeting using an erbB2-binding peptide (LTVSPWY) attached to the proapoptotic alpha-tocopheryl succinate (alpha-TOS). Treating erbB2-low or erbB2-high cells with alpha-TOS induced similar levels of apoptosis, whereas alpha-TOS-LTVSPWY induced greater levels of apoptosis in erbB2-high cells. alpha-TOS rapidly accumulated in erbB2-high cells exposed to alpha-TOS-LTVSPWY. The extent of apoptosis induced in erbB2-high cells by alpha-TOS-LTVSPWY was suppressed by erbB2 RNA interference as well as by inhibition of either endocytotic or lysosomal function. alpha-TOS-LTVSPWY reduced erbB2-high breast carcinomas in FVB/N c-neu transgenic mice. We conclude that a conjugate of a peptide targeting alpha-TOS to erbB2-overexpressing cancer cells induces rapid apoptosis and efficiently suppresses erbB2-positive breast tumors.
Wang
Xiu-Fang
XF
Apoptosis Research Group and Genomics Research Centre, School of Medical Science, Griffith University, Southport, Queensland, Australia.
Birringer
Marc
M
Dong
Lan-Feng
LF
Veprek
Pavel
P
Low
Pauline
P
Swettenham
Emma
E
Stantic
Marina
M
Yuan
Lin-Hong
LH
Zobalova
Renata
R
Wu
Kun
K
Ledvina
Miroslav
M
Ralph
Stephen J
SJ
Neuzil
Jiri
J
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000378:metabolism; D024505:Tocopherols; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D009842:Oligopeptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D024505:Tocopherols; D014810:Vitamin E