Tumor-Specific Peptide, Selected from a Phage Peptide Library, Enhances Antitumor Activity of Lactaptin

PLoS One. 2016 Aug 11;11(8):e0160980. doi: 10.1371/journal.pone.0160980. eCollection 2016.

Abstract

A recombinant analogue of lactaptin (RL2), a new potential anticancer molecule, induces apoptosis in cultured tumor cells. The tumor suppression efficacy of RL2 was shown against mouse hepatoma-1 cells and MDA-MB-231 human breast adenocarcinoma cells. The RL2-based therapeutic drug lactaptin is distributed evenly throughout the organism, which reduces its antitumor efficacy. In the current study, we obtained a genetic construct that allows production of the recombinant fusion protein T3-RL2, consisting of RL2 and T3 peptide (YTYDPWLIFPAN), in E. coli cells. T3 peptide was selected from a phage peptide library as a result of two screenings: in vitro using MDA-MB-231 cell culture and in vivo using a mouse xenograft model of breast cancer MDA-MB-231. It was shown that the displayed peptide T3 provides binding and internalization of phage particles by MDA-MB-231 cells and their specific accumulation in MDA-MB-231 tumor tissue. In addition, based on the nucleotide sequences coding RL2 and the known tumor-targeting peptide iRGD, we obtained genetic constructs that provide synthesis of fusion proteins RL2-iRGD and RL-iRGD-His. We studied the cytotoxic activity of fusion proteins T3-RL2, RL2-iRGD and RL-iRGD-His in vitro using MDA-MB-231 and MCF-7 human adenocarcinoma cells. The in vitro results showed that the fusion proteins inhibit proliferation of both cell cultures, and their cytotoxic activity is higher than that of RL2. In vivo experiments on the study of the antitumor efficacy of the obtained fusion proteins demonstrated that T3-RL2 protein significantly inhibits MDA-MB-231 tumor growth in a xenograft model compared with RL2, while the antitumor effect of RL2-iRGD and RL-iRGD-His proteins is comparable to the effect of RL2.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / prevention & control*
  • Caseins / metabolism*
  • Cell Proliferation / drug effects
  • Female
  • High-Throughput Screening Assays
  • Mice
  • Mice, Hairless
  • Mice, SCID
  • Peptide Fragments / pharmacology*
  • Peptide Library*
  • Recombinant Proteins
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Caseins
  • Peptide Fragments
  • Peptide Library
  • Recombinant Proteins
  • lactaptin, human

Grants and funding

The study was supported by the Ministry of Education and Science of the Russian Federation (http://xn--80abucjiibhv9a.xn--p1ai/) under the Federal Targeted Program “R&D in Priority Areas of Russian S&T Development”, contract 14.607.21.0063 (project unique identifier RFMEFI60714X0063). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.