Oncotarget

Research Papers:

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

Gejing De, Jae-Kyun Ko, Tao Tan, Hua Zhu, Haichang Li, Jianjie Ma _

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Oncotarget. 2014; 5:7734-7747. https://doi.org/10.18632/oncotarget.2301

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Abstract

Gejing De1, Jae-Kyun Ko2,3, Tao Tan4, Hua Zhu1, Haichang Li1 and Jianjie Ma1,2,4

1 Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA

2 Department of Physiology and Biophysics, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ, USA

3 Mutagenex Inc., 1 Jill Court, Hillsborough, NJ, USA

4 TRIM-edicine, Inc, Columbus, OH, USA

Correspondence:

Jianjie Ma, email:

Keywords: peptide, ATAP-iRGD, cancer therapy, integrin, apoptosis, mitochondria

Received: June 11, 2014 Accepted: July 31, 2014 Published: July 31, 2014

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.


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