Abstract
Background: The interfering peptides that block protein–protein interactions have been receiving increasing attention as potential therapeutic tools. Methods: We measured the internalization and biological effect of four bi-functional tumor-penetrating and interfering peptides into primary hepatocytes isolated from three non-malignant and 11 hepatocellular carcinomas. Results: These peptides are internalized in malignant hepatocytes but not in non-malignant cells. Furthermore, the degree of peptide internalization correlated with receptor expression level and tumor aggressiveness levels. Importantly, penetration of the peptides iRGD-IP, LinTT1-IP, TT1-IP, and RPARPAR-IP induced apoptosis of the malignant hepatocytes without effect on non-malignant cells. Conclusion: Receptor expression levels correlated with the level of peptide internalization and aggressiveness of the tumor. This study highlights the potential to exploit the expression of tumor-penetrating peptide receptors as a predictive marker of liver tumor aggressiveness. These bi-functional peptides could be developed for personalized tumor treatment.
Highlights
Despite significant progress in translational cancer research, advances in the design of targeted anti-cancer therapies have remained disappointingly slow [1,2,3,4,5,6]
One strategy is the use of Tumor-Penetrating Peptides (TPP), which are recognized as tumor-specific drug delivery vehicles that can penetrate into tumor cells to deliver cargo
Our results show that level of TPP-Interfering Peptide (IP) receptor expression by Hepatocellular Carcinoma (HCC) tumor cells correlates with degree of peptide internalization and tumor aggressiveness, which raises prospects for a selective liver tumor-targeting approach
Summary
Despite significant progress in translational cancer research, advances in the design of targeted anti-cancer therapies have remained disappointingly slow [1,2,3,4,5,6]. TPPs are internalized via specific receptors expressed on tumor cells and vasculature [7,8], and are characterized by the presence of the C-end Rule (CendR) motif with the consensus sequence R/KXXR/K [9,10]. This motif has to be C-terminally exposed to allow tumor-specific binding and penetration via the Neuropilin-1 (NRP-1) receptor. This study highlights the potential to exploit the expression of tumor-penetrating peptide receptors as a predictive marker of liver tumor aggressiveness. These bi-functional peptides could be developed for personalized tumor treatment
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