AC-1001 H3 CDR peptide induces apoptosis and signs of autophagy in vitro and exhibits antimetastatic activity in a syngeneic melanoma model.

Aline N Rabaça,Camyla F Farias,Denise C Arruda,Mariana H Massaoka,Dayane B Tada,Vera C Maia,Carlos R Figueiredo,Pedro I Silva Junior,Natalia Girola,Fernando Real,Luciano Polonelli,Renato A Mortara,Luiz R Travassos

doi:10.1002/2211-5463.12080

Abstract

Antibody‐derived peptides modulate functions of the immune system and are a source of anti‐infective and antitumor substances. Recent studies have shown that they comprise amino acid sequences of immunoglobulin complementarity‐determining regions, but also fragments of constant regions. VH CDR3 of murine mAb AC‐1001 displays antimetastatic activities using B16F10‐Nex2 murine melanoma cells in a syngeneic model. The peptide was cytotoxic in vitro in murine and human melanoma cells inducing reactive oxygen species (ROS) and apoptosis by the intrinsic pathway. Signs of autophagy were also suggested by the increased expression of LC3/LC3II and Beclin 1 and by ultrastructural evidence. AC‐1001 H3 bound to both G‐ and F‐actin and inhibited tumor cell migration. These results are important evidence of the antitumor activity of Ig CDR‐derived peptides.

Highlights

Antibody-derived peptides modulate functions of the immune system and are a source of anti-infective and antitumor substances
We demonstrated in the present work that AC-1001 H3 has antimetastatic effects using a syngeneic model with B16F10-Nex2 cells injected intravenously in male C57BL/6 mice
We demonstrated an enhanced expression of light chain 3 (LC3) and Beclin 1 proteins on peptide-treated cells (Fig. 7A,B)

Summary

Introduction

Antibody-derived peptides modulate functions of the immune system and are a source of anti-infective and antitumor substances. AC-1001 H3 bound to both G- and F-actin and inhibited tumor cell migration These results are important evidence of the antitumor activity of Ig CDR-derived peptides. Abbreviations CDR, complementary determining regions; DHE, dihydroethidium; Ig-VH, heavy chain variable region on immunoglobulin; MTT, 3-[4,5dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; pNA, para-nitroaniline; ROS, reactive oxygen species; TEM, transmission electron microscopy; TMRE, tetramethylrhodamine ethyl ester; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end-labeling. Anticancer peptides from natural sources are emerging as potential therapeutic agents, mainly because of their small size, low immunogenicity, better tissue penetration, and easy production, with the possibility of low-cost structural modifications. They can display a wide range of effects, such as necrotic, apoptotic, function blocking, anti-angiogenic, and immunostimulatory activities [9]

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Results

Conclusion