title: Amphipathic tail-anchoring peptide is a promising therapeutic agent for prostate cancer treatment.
abstract: 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.
authors.affiliation: Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Gejing
authors.initials: G
authors.lastname: De
authors.affiliation: Department of Physiology and Biophysics, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ, USA. Mutagenex Inc., 1 Jill Court, Hillsborough, NJ, USA.
authors.forename: Jae-Kyun
authors.initials: JK
authors.lastname: Ko
authors.affiliation: TRIM-edicine, Inc, Columbus, OH, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Tan
authors.affiliation: Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Haichang
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Department of Physiology and Biophysics, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ, USA. TRIM-edicine, Inc, Columbus, OH, USA.
authors.forename: Jianjie
authors.initials: J
authors.lastname: Ma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D015778:Minor Histocompatibility Antigens; D058990:Molecular Targeted Therapy / Q000379:methods*; D009842:Oligopeptides / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C096816:BCL2-related protein A1; D015778:Minor Histocompatibility Antigens; C569656:N-end cysteine peptide tumor-homing peptide; D009842:Oligopeptides; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2