Iterative Design and in Vivo Evaluation of an Oncolytic Antilymphoma Peptide

Abstract

Oncolytic peptides represent a promising new strategy within the field of cancer immunotherapy. Here we describe the systematic design and evaluation of short antilymphoma peptides within this paradigm. The peptides were tested in vitro and in vivo to identify a lead compound for further evaluation as novel oncolytic immunotherapeutic. In vitro tests revealed peptides with high activity against several lymphoma types and low cytotoxicity toward normal cells. Treated lymphoma cells exhibited a reduced mitochondrial membrane potential that resulted in an irreversible disintegration of their plasma membranes. No caspase activation or ultrastructural features of apoptotic cell death were observed. One of these peptides, 11, was shown to induce complete tumor regression and protective immunity following intralesional treatment of murine A20 B-lymphomas. Due to its selectivity for lymphoma cells and its ability to induce tumor-specific immune responses, 11 has the potential to be used in intralesional treatment of accessible lymphoma tumors.

Poroptosis: A form of cell death depending on plasma membrane nanopores formation

“…As shown in Figure 1 A, pM1 was cytotoxic to various cancer cell lines, causing almost 100% cell death at that concentration on both human cancer cell lines (SAOS2, H1299, MCF7, and A549) and mouse cancer cell lines (TC1, MC38, 4T1, and CT26), but did only mildly affect normal human cells (MRC5). This could be explained by the fact that cancer cell membranes often overexpressed negatively charged macromolecules, such as phosphatidyl serine and proteoglycans ( Dube and Bertozzi, 2005 ; Eksteen et al., 2017 ; Utsugi et al., 1991 ). The increasing of anionic character in cancer cells could make them be vulnerable to the positively charged pM1 than noncancerous cells.…”

Increasing C-Terminal Hydrophobicity Improves the Cell Permeability and Antiproliferative Activity of PACE4 Inhibitors against Prostate Cancer Cell Lines

“…Hydrophobic residues, when present in a CPP, increase the interactions with lipid bilayer and thus increasing translocation of peptides through membrane . Among hydrophobic residues, inclusion of Trp within basic peptides is a molecular determinant for enhancement of cell uptake efficiency. − For instance, more abundancy of Trp residues in amphiphilic helical CPPs increased their uptake in A549 cell lines . The exclusive role of tryptophan in cell penetration of polyarginine peptides is ascribed to the interaction with sulfated glycosaminoglycans possibly through hydrophobic and π–anion interactions in addition to its important hydrophobic interactions with lipid bilayer. , …”

Three Rounds of Stability-Guided Optimization and Systematical Evaluation of Oncolytic Peptide LTX-315

“…The SI value, which was defined as the ratio between the IC 50 values against normal human fibroblasts (MRC-5) and IC 50 values against A20 lymphoma cells, was applied for the preliminary evaluation of the selective cytotoxicity of oncolytic peptides. 29 The SI values for FXY-13, FXY-14, and FXY-18 were higher than that of LTX-315, indicating that the C-terminal hydrazidation may improve the selectivity of LTX-315. Meanwhile, the N-terminal acetylation (FXY-17) and polyethylene glycol modification (FXY-19) may impair the selectivity of LTX-315, while the D-type amino acid substitution (FXY-12) may slightly improve the selectivity of LTX-315.…”

“…Recently, oncolytic peptides possessing synergistic oncolytic-immunotherapy effect have emerged as one of the main subsets of anticancer peptides and potential anticancer agents. ,, Oncolytic peptides are a class of surface-acting membrane-disrupting peptides, such as CAMP-derived peptide (LL-37), bovine lactotransferrin (LTF)-derived peptides, animal venoms and toxins-derived peptides, as well as the synthetic oncolytic peptides represented by “peptide 11″, , SVS-1 and (KAAKKAA) 3 . , Oncolytic peptides could disrupt the integrity of cancer cell membrane, penetrate cells, and destroy the intracellular membrane, the combined actions of which could induce the rapid death of cancer cells. , …”