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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2007-04, Vol.67 (7), p.3337-3344
Main Authors: WANG, Xiu-Fang, BIRRINGER, Marc, LEDVINA, Miroslav, RALPH, Stephen J, NEUZIL, Jiri, DONG, Lan-Feng, VEPREK, Pavel, LOW, Pauline, SWETTENHAM, Emma, STANTIC, Marina, YUAN, Lin-Hong, ZOBALOVA, Renata, KUN WU
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Breast Neoplasms - drug therapy
Breast Neoplasms - enzymology
Breast Neoplasms - metabolism
Cell Line, Tumor
Gynecology. Andrology. Obstetrics
Humans
Mammary gland diseases
Medical sciences
Oligopeptides - administration & dosage
Oligopeptides - pharmacokinetics
Pharmacology. Drug treatments
Protein Binding
Receptor, ErbB-2 - biosynthesis
Receptor, ErbB-2 - metabolism
Tocopherols
Tumors
Vitamin E - administration & dosage
Vitamin E - analogs & derivatives
Vitamin E - pharmacokinetics
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-06-2480