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A novel recombinant slow-release TNF α-derived peptide effectively inhibits tumor growth and angiogensis.

Ma Y, Zhao S, Shen S, Fang S, Ye Z, Shi Z, Hong A - Sci Rep (2015)

Bottom Line: 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.These findings suggest that RMP16 may represent a promising long-lasting antitumor therapeutic peptide with less TNF α-induced toxicity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedicine &Dept. Cellular Biology, Jinan University.

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.

No MeSH data available.


Related in: MedlinePlus

Assays for ensymolysis half-life and receptors competitive binding of RMP16 and its effects on growth of multiple tumor cells, vascular endothelial cell and normal human mammary epithelial cell.(A) In vitro ensymolysis half-life of RMP16 binding with or without HSA by Factor Xa. RMP16 significantly inhibit the proliferation of prostate cancer Du145, lymphoma Raji, leukemia K562, esophageal Eca109, cervical cancer HeLa, breast cancer MCF-7 and MDA-MB-231 cells (B) and HUVEC cells (C) with different half inhibitory concentration (IC50). (D) RMP16 has no significant inhibition effect on human mammary non-tumorigenic epithelial cells MCF10A. (E) Displacement of [125I] TNF α by RMP16 and TNF α from human TNFRI or TNFRII of ML-la cells by anti-p60 antibody or anti-p80 antibody blocking TNFRI or TNFRII, respectively. Results in (E) are expressed as percentage of maximum binding to [125I] TNF α. **P < 0.01, RMP16 vs P16 (Dunnett’s test, n = 3).
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f2: Assays for ensymolysis half-life and receptors competitive binding of RMP16 and its effects on growth of multiple tumor cells, vascular endothelial cell and normal human mammary epithelial cell.(A) In vitro ensymolysis half-life of RMP16 binding with or without HSA by Factor Xa. RMP16 significantly inhibit the proliferation of prostate cancer Du145, lymphoma Raji, leukemia K562, esophageal Eca109, cervical cancer HeLa, breast cancer MCF-7 and MDA-MB-231 cells (B) and HUVEC cells (C) with different half inhibitory concentration (IC50). (D) RMP16 has no significant inhibition effect on human mammary non-tumorigenic epithelial cells MCF10A. (E) Displacement of [125I] TNF α by RMP16 and TNF α from human TNFRI or TNFRII of ML-la cells by anti-p60 antibody or anti-p80 antibody blocking TNFRI or TNFRII, respectively. Results in (E) are expressed as percentage of maximum binding to [125I] TNF α. **P < 0.01, RMP16 vs P16 (Dunnett’s test, n = 3).

Mentions: The polypeptide concentrations in the solution were determined by LC-MS, and the in-vitro half-life of RMP16 was determined. In the presence of HSA, the factor Xa enzyme digestion half-life of RMP16 was significantly prolonged to 15.83 h from 9.72 h (Fig. 2A). The results indicated that the presence of 7-mer peptide WQRPSSW and the slow-release linker IEGR can efficiently extend the half-life of the active polypeptide P16.


A novel recombinant slow-release TNF α-derived peptide effectively inhibits tumor growth and angiogensis.

Ma Y, Zhao S, Shen S, Fang S, Ye Z, Shi Z, Hong A - Sci Rep (2015)

Assays for ensymolysis half-life and receptors competitive binding of RMP16 and its effects on growth of multiple tumor cells, vascular endothelial cell and normal human mammary epithelial cell.(A) In vitro ensymolysis half-life of RMP16 binding with or without HSA by Factor Xa. RMP16 significantly inhibit the proliferation of prostate cancer Du145, lymphoma Raji, leukemia K562, esophageal Eca109, cervical cancer HeLa, breast cancer MCF-7 and MDA-MB-231 cells (B) and HUVEC cells (C) with different half inhibitory concentration (IC50). (D) RMP16 has no significant inhibition effect on human mammary non-tumorigenic epithelial cells MCF10A. (E) Displacement of [125I] TNF α by RMP16 and TNF α from human TNFRI or TNFRII of ML-la cells by anti-p60 antibody or anti-p80 antibody blocking TNFRI or TNFRII, respectively. Results in (E) are expressed as percentage of maximum binding to [125I] TNF α. **P < 0.01, RMP16 vs P16 (Dunnett’s test, n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4559766&req=5

f2: Assays for ensymolysis half-life and receptors competitive binding of RMP16 and its effects on growth of multiple tumor cells, vascular endothelial cell and normal human mammary epithelial cell.(A) In vitro ensymolysis half-life of RMP16 binding with or without HSA by Factor Xa. RMP16 significantly inhibit the proliferation of prostate cancer Du145, lymphoma Raji, leukemia K562, esophageal Eca109, cervical cancer HeLa, breast cancer MCF-7 and MDA-MB-231 cells (B) and HUVEC cells (C) with different half inhibitory concentration (IC50). (D) RMP16 has no significant inhibition effect on human mammary non-tumorigenic epithelial cells MCF10A. (E) Displacement of [125I] TNF α by RMP16 and TNF α from human TNFRI or TNFRII of ML-la cells by anti-p60 antibody or anti-p80 antibody blocking TNFRI or TNFRII, respectively. Results in (E) are expressed as percentage of maximum binding to [125I] TNF α. **P < 0.01, RMP16 vs P16 (Dunnett’s test, n = 3).
Mentions: The polypeptide concentrations in the solution were determined by LC-MS, and the in-vitro half-life of RMP16 was determined. In the presence of HSA, the factor Xa enzyme digestion half-life of RMP16 was significantly prolonged to 15.83 h from 9.72 h (Fig. 2A). The results indicated that the presence of 7-mer peptide WQRPSSW and the slow-release linker IEGR can efficiently extend the half-life of the active polypeptide P16.

Bottom Line: 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.These findings suggest that RMP16 may represent a promising long-lasting antitumor therapeutic peptide with less TNF α-induced toxicity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedicine &Dept. Cellular Biology, Jinan University.

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.

No MeSH data available.


Related in: MedlinePlus