Hadianamrei, R., Anas Tomeh, M., Brown, S. orcid.org/0000-0002-7581-7491 et al. (2 more authors) (2022) Rationally designed short cationic α-helical peptides with selective anticancer activity. Journal of Colloid and Interface Science, 607 (Part 1). pp. 488-501. ISSN 0021-9797
Abstract
Hypothesis
Naturally derived or synthetic anticancer peptides (ACPs) have emerged as a new generation of anticancer agents with higher selectivity for cancer cells and less propensity for drug resistance. Despite the structural diversity of ACPs, α-helix is the most common secondary structure among them. Herein we report the development of a new library of short cationic amphiphilic α-helical ACPs with selective cytotoxicity against colorectal and cervical cancer.
Experiments
The peptides had a general formula C(XXYY)3 with C representing amino acid cysteine (providing a -SH group for molecular conjugation), X representing hydrophobic amino acids (isoleucine (I) or leucine (L)), and Y representing cationic amino acids (arginine (R) or lysine (K)). Two variants of the peptides were synthesized by adding additional Isoleucine residues to the C-terminal and replacing the N-terminal cysteine with LC-propargylglycine (LC-G) to investigate the effect of N-terminal and C-terminal variation on the anticancer activity. The structure and physicochemical properties of the peptides were determined by RP-HPLC, LC-MS and CD spectroscopy. The cytotoxicity of the peptides in different cell lines was assessed by MTT test, cell proliferation assay and mitochondrial damage assay. The mechanism of cell selectivity of the peptides was investigated by studying their interfacial behaviour at the air/water and lipid/water interface using Langmuir trough.
Findings
The peptides consisting of K residues in their hydrophilic domains exhibited more selective anticancer activity whereas the peptides containing R exhibited strong toxicity in normal cells. The anticancer activity of the peptides was a function of their helical content and their hydrophobicity. Therefore, the addition of two I residues at C-terminal enhanced the anticancer activity of the peptides by increasing their hydrophobicity and their helical content. These two variants also exhibited strong anticancer activity against colorectal cancer multicellular tumour spheroids (MCTS). The higher toxicity of the peptides in cancer cells compared to normal cells was the result of higher penetration into the negatively charged cancer cell membranes, leading to higher cellular uptake, and their cytotoxic effect was mainly exerted by damaging the mitochondrial membranes leading to apoptosis. The results from this study provide a basis for rational design of new α-helical ACPs with enhanced anticancer activity and selectivity.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
Keywords: | Anticancer peptides; Cationic amphiphilic peptides; Helical peptides; Membrane penetration; Cancer cell targeting |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number Engineering and Physical Sciences Research Council EP/N023579/1; EP/N007174/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 16 Sep 2021 06:53 |
Last Modified: | 16 Sep 2021 06:53 |
Status: | Published |
Publisher: | Elsevier BV |
Refereed: | Yes |
Identification Number: | 10.1016/j.jcis.2021.08.200 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:178258 |