Cargando…
Analogs of a Natural Peptaibol Exert Anticancer Activity in Both Cisplatin- and Doxorubicin-Resistant Cells and in Multicellular Tumor Spheroids
Peptaibols, by disturbing the permeability of phospholipid membranes, can overcome anticancer drug resistance, but their natural hydrophobicity hampers their administration. By a green peptide synthesis protocol, we produced two water-soluble analogs of the peptaibol trichogin GA IV, termed K6-Lol a...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394784/ https://www.ncbi.nlm.nih.gov/pubmed/34445069 http://dx.doi.org/10.3390/ijms22168362 |
_version_ | 1783744026723221504 |
---|---|
author | Casagrande, Naike Borghese, Cinzia Gabbatore, Laura Morbiato, Laura De Zotti, Marta Aldinucci, Donatella |
author_facet | Casagrande, Naike Borghese, Cinzia Gabbatore, Laura Morbiato, Laura De Zotti, Marta Aldinucci, Donatella |
author_sort | Casagrande, Naike |
collection | PubMed |
description | Peptaibols, by disturbing the permeability of phospholipid membranes, can overcome anticancer drug resistance, but their natural hydrophobicity hampers their administration. By a green peptide synthesis protocol, we produced two water-soluble analogs of the peptaibol trichogin GA IV, termed K6-Lol and K6-NH2. To reduce production costs, we successfully explored the possibility of changing the naturally occurring 1,2-aminoalcohol leucinol to a C-terminal amide. Peptaibol activity was evaluated in ovarian cancer (OvCa) and Hodgkin lymphoma (HL) cell lines. Peptaibols exerted comparable cytotoxic effects in cancer cell lines that were sensitive—and had acquired resistance—to cisplatin and doxorubicin, as well as in the extrinsic-drug-resistant OvCa 3-dimensional spheroids. Peptaibols, rapidly taken up by tumor cells, deeply penetrated and killed OvCa-spheroids. They led to cell membrane permeabilization and phosphatidylserine exposure and were taken up faster by cancer cells than normal cells. They were resistant to proteolysis and maintained a stable helical structure in the presence of cancer cells. In conclusion, these promising results strongly point out the need for further preclinical evaluation of our peptaibols as new anticancer agents. |
format | Online Article Text |
id | pubmed-8394784 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-83947842021-08-28 Analogs of a Natural Peptaibol Exert Anticancer Activity in Both Cisplatin- and Doxorubicin-Resistant Cells and in Multicellular Tumor Spheroids Casagrande, Naike Borghese, Cinzia Gabbatore, Laura Morbiato, Laura De Zotti, Marta Aldinucci, Donatella Int J Mol Sci Article Peptaibols, by disturbing the permeability of phospholipid membranes, can overcome anticancer drug resistance, but their natural hydrophobicity hampers their administration. By a green peptide synthesis protocol, we produced two water-soluble analogs of the peptaibol trichogin GA IV, termed K6-Lol and K6-NH2. To reduce production costs, we successfully explored the possibility of changing the naturally occurring 1,2-aminoalcohol leucinol to a C-terminal amide. Peptaibol activity was evaluated in ovarian cancer (OvCa) and Hodgkin lymphoma (HL) cell lines. Peptaibols exerted comparable cytotoxic effects in cancer cell lines that were sensitive—and had acquired resistance—to cisplatin and doxorubicin, as well as in the extrinsic-drug-resistant OvCa 3-dimensional spheroids. Peptaibols, rapidly taken up by tumor cells, deeply penetrated and killed OvCa-spheroids. They led to cell membrane permeabilization and phosphatidylserine exposure and were taken up faster by cancer cells than normal cells. They were resistant to proteolysis and maintained a stable helical structure in the presence of cancer cells. In conclusion, these promising results strongly point out the need for further preclinical evaluation of our peptaibols as new anticancer agents. MDPI 2021-08-04 /pmc/articles/PMC8394784/ /pubmed/34445069 http://dx.doi.org/10.3390/ijms22168362 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Casagrande, Naike Borghese, Cinzia Gabbatore, Laura Morbiato, Laura De Zotti, Marta Aldinucci, Donatella Analogs of a Natural Peptaibol Exert Anticancer Activity in Both Cisplatin- and Doxorubicin-Resistant Cells and in Multicellular Tumor Spheroids |
title | Analogs of a Natural Peptaibol Exert Anticancer Activity in Both Cisplatin- and Doxorubicin-Resistant Cells and in Multicellular Tumor Spheroids |
title_full | Analogs of a Natural Peptaibol Exert Anticancer Activity in Both Cisplatin- and Doxorubicin-Resistant Cells and in Multicellular Tumor Spheroids |
title_fullStr | Analogs of a Natural Peptaibol Exert Anticancer Activity in Both Cisplatin- and Doxorubicin-Resistant Cells and in Multicellular Tumor Spheroids |
title_full_unstemmed | Analogs of a Natural Peptaibol Exert Anticancer Activity in Both Cisplatin- and Doxorubicin-Resistant Cells and in Multicellular Tumor Spheroids |
title_short | Analogs of a Natural Peptaibol Exert Anticancer Activity in Both Cisplatin- and Doxorubicin-Resistant Cells and in Multicellular Tumor Spheroids |
title_sort | analogs of a natural peptaibol exert anticancer activity in both cisplatin- and doxorubicin-resistant cells and in multicellular tumor spheroids |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394784/ https://www.ncbi.nlm.nih.gov/pubmed/34445069 http://dx.doi.org/10.3390/ijms22168362 |
work_keys_str_mv | AT casagrandenaike analogsofanaturalpeptaibolexertanticanceractivityinbothcisplatinanddoxorubicinresistantcellsandinmulticellulartumorspheroids AT borghesecinzia analogsofanaturalpeptaibolexertanticanceractivityinbothcisplatinanddoxorubicinresistantcellsandinmulticellulartumorspheroids AT gabbatorelaura analogsofanaturalpeptaibolexertanticanceractivityinbothcisplatinanddoxorubicinresistantcellsandinmulticellulartumorspheroids AT morbiatolaura analogsofanaturalpeptaibolexertanticanceractivityinbothcisplatinanddoxorubicinresistantcellsandinmulticellulartumorspheroids AT dezottimarta analogsofanaturalpeptaibolexertanticanceractivityinbothcisplatinanddoxorubicinresistantcellsandinmulticellulartumorspheroids AT aldinuccidonatella analogsofanaturalpeptaibolexertanticanceractivityinbothcisplatinanddoxorubicinresistantcellsandinmulticellulartumorspheroids |