Abstract
RMP16, a recombinant TNF α-derived polypeptide comprising a specific human serum albumin (HSA)-binding 7-mer peptide identified by phage display screening (WQRPSSW), a cleavage peptide for Factor Xa (IEGR), and a 20-amino acid bioactive peptide P16 (TNF α segment including amino acid residues 75–94), was prepared by gene-engineering technology. RMP16 showed prolonged half-life, 13.11 hours in mice (half-lives of P16 and TNF α are 5.77 and 29.0 minutes, respectively), and obviously higher receptor selectivity for TNFRI than TNF α. RMP16 had significant inhibition effects for multiple tumor cells, especially prostate cancer Du145 cells, and human vascular endothelial cells but not for human mammary non-tumorigenic epithelial cells. RMP16 can more effectively induce apoptosis and inhibit proliferation for DU145 cells than P16 and TNF α via the caspase-dependent apoptosis pathway and G0/G1 cell cycle arrest. In nude mice with transplanted tumor of DU145 cells, RMP16 significantly induced apoptosis and necrosis of tumor tissues but causing less side effects, and tumor inhibitory rate reached nearly 80%, furthermore, RMP16 can potently inhibit tumor angiogenesis and neovascularization. These findings suggest that RMP16 may represent a promising long-lasting antitumor therapeutic peptide with less TNF α-induced toxicity.
Highlights
The tumor necrosis factor alpha (TNF α ) plays an important role in multiple physiological and pathological processes[1,2]
To overcome the limitations of P16 and TNF α in therapeutic application, in current study, we have developed a recombinant peptide RMP16 with 31 amino acids by addition of a specific human serum albumin (HSA)-binding 7-mer peptide (WQRPSSW) at the N-terminus, followed by a slow-release linker (-IEGR-) which is the sensitive recognition sequence of plasma factor Xa (FXa), and bioactive peptide P16
One phage encoded for a 7-mer peptide with the amino acid sequence of HLYWQRP, whereas the other two phages encoded a 7-mer peptide with the same amino acid sequence of WQRPSSW
Summary
The tumor necrosis factor alpha (TNF α ) plays an important role in multiple physiological and pathological processes[1,2]. The precursor of TNF α protein is consisted of 233 amino acid residues including a signaling peptide. The biological activities of TNF α depend on its binding to two specific receptors on cell membrane, the tumor necrosis factor receptor I and II (TNFRI and TNFRII)[7]. TNF α is one of the most promising drug for cancer treatment[14,15]. In 1980 s, the genetic engineering products of TNF α have been used in the clinic treatment of cancers. Our studies indicated that TNF α segment containing amino acid residues 75–94 (named as P16, LLTHTISRIAVSYQTKVNLL) could selectively bind to TNFRI and has good anti-cancer activity (unpublished data). Because P16 has a relatively small molecular weight of 2270.7 Da., it shows very short half-life (∼ 5.77 minutes) and low bioavailability due to rapid renal clearance and hepatic metabolism
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