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.
Highlights
A major focus in current cancer research is to develop small molecules or peptides as potential therapeutic agents or diagnostic tools for cancer treatment [1,2,3,4,5]
We showed that Amphipathic tail-anchoring peptide (ATAP)-internalizing RGD (iRGD) is effective in suppressing growth of multiple cancer cell lines in vitro, including DU145 which has been proved to be resistant to Bcl-2 homology domain-3 (BH3) derived peptide[36]
The ATAP-iRGD-M8 peptide is soluble in physiological saline solution, and maintains potent pro-apoptotic activity in prostate cancer cells with limited off-target toxicity on normal tissues
Summary
A major focus in current cancer research is to develop small molecules or peptides as potential therapeutic agents or diagnostic tools for cancer treatment [1,2,3,4,5]. RGDmediated recognition of tumor cells could be used as imaging tools for cancer diagnosis [15,16,17]. A disulfide-based cyclic RGD peptide referred to as internalizing RGD (iRGD) has shown improved efficacy in selectively delivering therapeutic or imaging agents to tumor site [17]. IRGD contained a sequence of nine amino acids, CRGDKGPDC, that facilitates interaction with neuropilin-1 receptor on the target tumor cells and thereby increase cell membrane permeability [18, 19]. Coating of nanoparticles containing paclitaxel with iRGD could enhance homing of the chemotherapeutic agent to tumor tissues [18], and co-administration of iRGD with doxorubicin and trastuzumab improved efficacy of these cancer drugs [20]
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