Amphipathic tail-anchoring peptide is a promising therapeutic agent for prostate cancer treatment

Amphipathic tail-anchoring peptide (ATAP) derived from the human anti-apoptotic protein Bfl-1 is a potent inducer of apoptosis by targeting mitochondria permeability transition. By linking ATAP to an internalizing RGD peptide (iRGD), selective targeting for ATAP to tumor cell was achieved. Confocal...

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Bibliographic Details
Published inOncotarget Vol. 5; no. 17; pp. 7734 - 7747
Main Authors De, Gejing, Ko, Jae-Kyun, Tan, Tao, Zhu, Hua, Li, Haichang, Ma, Jianjie
Format Journal Article
LanguageEnglish
Published United States Impact Journals LLC 15.09.2014
Subjects
Animals
Antineoplastic Agents - pharmacology
Humans
Male
Mice
Mice, Nude
Microscopy, Confocal
Minor Histocompatibility Antigens
Molecular Targeted Therapy - methods
Oligopeptides - pharmacology
Peptides - pharmacology
Prostatic Neoplasms - pathology
Proto-Oncogene Proteins c-bcl-2 - chemistry
Research Paper
Xenograft Model Antitumor Assays
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Summary:Amphipathic tail-anchoring peptide (ATAP) derived from the human anti-apoptotic protein Bfl-1 is a potent inducer of apoptosis by targeting mitochondria permeability transition. By linking ATAP to an internalizing RGD peptide (iRGD), selective targeting for ATAP to tumor cell was achieved. Confocal fluorescence microscopy showed that ATAP-iRGD could penetrate into cancer cells and distribute along the mitochondria network. ATAP-iRGD triggered mitochondria-dependent cell death through release of cytochrome c. In an effort to promote ATAP-iRGD physiochemical properties to approach clinic application, amino acid substitution and chemical modification were made with ATAP-iRGD to improve its bioactivity. One of these modified peptides, ATAP-iRGD-M8, was with improved stability and aqueous solubility without compromising in vitro cytotoxicity in cultured cancer cells. In vivo xenograft studies with multiple prostate cancer cell lines showed that intravenous administration of ATAP-iRGD-M8 suppressed tumor growth. Toxicological studies revealed that repetitive intravenous administration of ATAP-iRGD-M8 did not produce significant toxicity in the SV129 mice. Our data suggest that ATAP-iRGD-M8 is a promising agent with high selectivity and limited systemic toxicity for prostate cancer treatment.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.2301