New Perspective for Using Antimicrobial and Cell-Penetrating Peptides to Increase Efficacy of Antineoplastic 5-FU in Cancer Cells

Author:

Vale Nuno123ORCID,Ribeiro Eduarda124ORCID,Cruz Inês12,Stulberg Valentina5,Koksch Beate5,Costa Bárbara123ORCID

Affiliation:

1. PerMed Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal

2. CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Hernâni Monteiro, 4200-319 Porto, Portugal

3. Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal

4. ICBAS—School of Medicine and Biomedical Sciences, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal

5. Institute of Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 20, 14195 Berlin, Germany

Abstract

This study explores the effectiveness of the antineoplastic agent 5-FU in cancer cells by leveraging the unique properties of cationic antimicrobial peptides (CAMPs) and cell-penetrating peptides (CPPs). Traditional anticancer therapies face substantial limitations, including unfavorable pharmacokinetic profiles and inadequate specificity for tumor sites. These drawbacks often necessitate higher therapeutic agent doses, leading to severe toxicity in normal cells and adverse side effects. Peptides have emerged as promising carriers for targeted drug delivery, with their ability to selectively deliver therapeutics to cells expressing specific receptors. This enhances intracellular drug delivery, minimizes drug resistance, and reduces toxicity. In this research, we comprehensively evaluate the ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of various AMPs and CPPs to gain insights into their potential as anticancer agents. The peptide synthesis involved a solid-phase synthesis using a Liberty Microwave Peptide Synthesizer. The peptide purity was confirmed via LC-MS and HPLC methods. For the ADMET screening, computational tools were employed, assessing parameters like absorption, distribution, metabolism, excretion, and toxicity. The cell lines A549 and UM-UC-5 were cultured and treated with 5-FU, CAMPs, and CPPs. The cell viability was measured using the MTT assay. The physicochemical properties analysis revealed favorable drug-likeness attributes. The peptides exhibited potential inhibitory activity against CYP3A4. The ADMET predictions indicated variable absorption and distribution characteristics. Furthermore, we assessed the effectiveness of these peptides alone and in combination with 5-FU, a widely used antineoplastic agent, in two distinct cancer cell lines, UM-UC-5 and A549. Our findings indicate that CAMPs can significantly reduce the cell viability in A549 cells, while CPPs exhibit promising results in UM-UC-5 cells. Understanding these multifaceted effects could open new avenues for antiviral and anticancer research. Further, experimental validation is necessary to confirm the mechanism of action of these peptides, especially in combination with 5-FU.

Publisher

MDPI AG

Subject

Biomedical Engineering,Biomaterials

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