Cargando…

Design and development of a peptide-based adiponectin receptor agonist for cancer treatment

BACKGROUND: Adiponectin, a fat tissue-derived adipokine, exhibits beneficial effects against insulin resistance, cardiovascular disease, inflammatory conditions, and cancer. Circulating adiponectin levels are decreased in obese individuals, and this feature correlates with increased risk of developi...

Descripción completa

Detalles Bibliográficos
Autores principales: Otvos, Laszlo, Haspinger, Eva, La Russa, Francesca, Maspero, Federica, Graziano, Patrizia, Kovalszky, Ilona, Lovas, Sandor, Nama, Kaushik, Hoffmann, Ralf, Knappe, Daniel, Cassone, Marco, Wade, John, Surmacz, Eva
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198688/
https://www.ncbi.nlm.nih.gov/pubmed/21974986
http://dx.doi.org/10.1186/1472-6750-11-90
_version_ 1782214472286339072
author Otvos, Laszlo
Haspinger, Eva
La Russa, Francesca
Maspero, Federica
Graziano, Patrizia
Kovalszky, Ilona
Lovas, Sandor
Nama, Kaushik
Hoffmann, Ralf
Knappe, Daniel
Cassone, Marco
Wade, John
Surmacz, Eva
author_facet Otvos, Laszlo
Haspinger, Eva
La Russa, Francesca
Maspero, Federica
Graziano, Patrizia
Kovalszky, Ilona
Lovas, Sandor
Nama, Kaushik
Hoffmann, Ralf
Knappe, Daniel
Cassone, Marco
Wade, John
Surmacz, Eva
author_sort Otvos, Laszlo
collection PubMed
description BACKGROUND: Adiponectin, a fat tissue-derived adipokine, exhibits beneficial effects against insulin resistance, cardiovascular disease, inflammatory conditions, and cancer. Circulating adiponectin levels are decreased in obese individuals, and this feature correlates with increased risk of developing several metabolic, immunological and neoplastic diseases. Thus, pharmacological replacement of adiponectin might prove clinically beneficial, especially for the obese patient population. At present, adiponectin-based therapeutics are not available, partly due to yet unclear structure/function relationships of the cytokine and difficulties in converting the full size adiponectin protein into a viable drug. RESULTS: We aimed to generate adiponectin-based short peptide that can mimic adiponectin action and be suitable for preclinical and clinical development as a cancer therapeutic. Using a panel of 66 overlapping 10 amino acid-long peptides covering the entire adiponectin globular domain (residues 105-254), we identified the 149-166 region as the adiponectin active site. Three-dimensional modeling of the active site and functional screening of additional 330 peptide analogs covering this region resulted in the development of a lead peptidomimetic, ADP 355 (H-DAsn-Ile-Pro-Nva-Leu-Tyr-DSer-Phe-Ala-DSer-NH(2)). In several adiponectin receptor-positive cancer cell lines, ADP 355 restricted proliferation in a dose-dependent manner at 100 nM-10 μM concentrations (exceeding the effects of 50 ng/mL globular adiponectin). Furthermore, ADP 355 modulated several key signaling pathways (AMPK, Akt, STAT3, ERK1/2) in an adiponectin-like manner. siRNA knockdown experiments suggested that ADP 355 effects can be transmitted through both adiponectin receptors, with a greater contribution of AdipoR1. In vivo, intraperitoneal administration of 1 mg/kg/day ADP 355 for 28 days suppressed the growth of orthotopic human breast cancer xenografts by ~31%. The peptide displayed excellent stability (at least 30 min) in mouse blood or serum and did not induce gross toxic effects at 5-50 mg/kg bolus doses in normal CBA/J mice. CONCLUSIONS: ADP 355 is a first-in-class adiponectin receptor agonist. Its biological activity, superior stability in biological fluids as well as acceptable toxicity profile indicate that the peptidomimetic represents a true lead compound for pharmaceutical development to replace low adiponectin levels in cancer and other malignancies.
format Online
Article
Text
id pubmed-3198688
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-31986882011-10-23 Design and development of a peptide-based adiponectin receptor agonist for cancer treatment Otvos, Laszlo Haspinger, Eva La Russa, Francesca Maspero, Federica Graziano, Patrizia Kovalszky, Ilona Lovas, Sandor Nama, Kaushik Hoffmann, Ralf Knappe, Daniel Cassone, Marco Wade, John Surmacz, Eva BMC Biotechnol Research Article BACKGROUND: Adiponectin, a fat tissue-derived adipokine, exhibits beneficial effects against insulin resistance, cardiovascular disease, inflammatory conditions, and cancer. Circulating adiponectin levels are decreased in obese individuals, and this feature correlates with increased risk of developing several metabolic, immunological and neoplastic diseases. Thus, pharmacological replacement of adiponectin might prove clinically beneficial, especially for the obese patient population. At present, adiponectin-based therapeutics are not available, partly due to yet unclear structure/function relationships of the cytokine and difficulties in converting the full size adiponectin protein into a viable drug. RESULTS: We aimed to generate adiponectin-based short peptide that can mimic adiponectin action and be suitable for preclinical and clinical development as a cancer therapeutic. Using a panel of 66 overlapping 10 amino acid-long peptides covering the entire adiponectin globular domain (residues 105-254), we identified the 149-166 region as the adiponectin active site. Three-dimensional modeling of the active site and functional screening of additional 330 peptide analogs covering this region resulted in the development of a lead peptidomimetic, ADP 355 (H-DAsn-Ile-Pro-Nva-Leu-Tyr-DSer-Phe-Ala-DSer-NH(2)). In several adiponectin receptor-positive cancer cell lines, ADP 355 restricted proliferation in a dose-dependent manner at 100 nM-10 μM concentrations (exceeding the effects of 50 ng/mL globular adiponectin). Furthermore, ADP 355 modulated several key signaling pathways (AMPK, Akt, STAT3, ERK1/2) in an adiponectin-like manner. siRNA knockdown experiments suggested that ADP 355 effects can be transmitted through both adiponectin receptors, with a greater contribution of AdipoR1. In vivo, intraperitoneal administration of 1 mg/kg/day ADP 355 for 28 days suppressed the growth of orthotopic human breast cancer xenografts by ~31%. The peptide displayed excellent stability (at least 30 min) in mouse blood or serum and did not induce gross toxic effects at 5-50 mg/kg bolus doses in normal CBA/J mice. CONCLUSIONS: ADP 355 is a first-in-class adiponectin receptor agonist. Its biological activity, superior stability in biological fluids as well as acceptable toxicity profile indicate that the peptidomimetic represents a true lead compound for pharmaceutical development to replace low adiponectin levels in cancer and other malignancies. BioMed Central 2011-10-05 /pmc/articles/PMC3198688/ /pubmed/21974986 http://dx.doi.org/10.1186/1472-6750-11-90 Text en Copyright ©2011 Otvos et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Otvos, Laszlo
Haspinger, Eva
La Russa, Francesca
Maspero, Federica
Graziano, Patrizia
Kovalszky, Ilona
Lovas, Sandor
Nama, Kaushik
Hoffmann, Ralf
Knappe, Daniel
Cassone, Marco
Wade, John
Surmacz, Eva
Design and development of a peptide-based adiponectin receptor agonist for cancer treatment
title Design and development of a peptide-based adiponectin receptor agonist for cancer treatment
title_full Design and development of a peptide-based adiponectin receptor agonist for cancer treatment
title_fullStr Design and development of a peptide-based adiponectin receptor agonist for cancer treatment
title_full_unstemmed Design and development of a peptide-based adiponectin receptor agonist for cancer treatment
title_short Design and development of a peptide-based adiponectin receptor agonist for cancer treatment
title_sort design and development of a peptide-based adiponectin receptor agonist for cancer treatment
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198688/
https://www.ncbi.nlm.nih.gov/pubmed/21974986
http://dx.doi.org/10.1186/1472-6750-11-90
work_keys_str_mv AT otvoslaszlo designanddevelopmentofapeptidebasedadiponectinreceptoragonistforcancertreatment
AT haspingereva designanddevelopmentofapeptidebasedadiponectinreceptoragonistforcancertreatment
AT larussafrancesca designanddevelopmentofapeptidebasedadiponectinreceptoragonistforcancertreatment
AT masperofederica designanddevelopmentofapeptidebasedadiponectinreceptoragonistforcancertreatment
AT grazianopatrizia designanddevelopmentofapeptidebasedadiponectinreceptoragonistforcancertreatment
AT kovalszkyilona designanddevelopmentofapeptidebasedadiponectinreceptoragonistforcancertreatment
AT lovassandor designanddevelopmentofapeptidebasedadiponectinreceptoragonistforcancertreatment
AT namakaushik designanddevelopmentofapeptidebasedadiponectinreceptoragonistforcancertreatment
AT hoffmannralf designanddevelopmentofapeptidebasedadiponectinreceptoragonistforcancertreatment
AT knappedaniel designanddevelopmentofapeptidebasedadiponectinreceptoragonistforcancertreatment
AT cassonemarco designanddevelopmentofapeptidebasedadiponectinreceptoragonistforcancertreatment
AT wadejohn designanddevelopmentofapeptidebasedadiponectinreceptoragonistforcancertreatment
AT surmaczeva designanddevelopmentofapeptidebasedadiponectinreceptoragonistforcancertreatment