Antitumor Activity and Mechanism of Action of Hormonotoxin, an LHRH Analog Conjugated to Dermaseptin-B2, a Multifunctional Antimicrobial Peptide

Prostate cancer is the most common cancer in men. For patients with advanced or metastatic prostate cancer, available treatments can slow down its progression but cannot cure it. The development of innovative drugs resulting from the exploration of biodiversity could open new therapeutic alternative...

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Autores principales:	Mickael Couty, Marie Dusaud, Mickael Miro-Padovani, Liuhui Zhang, Patricia Zadigue, Loussiné Zargarian, Olivier Lequin, Alexandre de la Taille, Jean Delbe, Yamina Hamma-Kourbali, Mohamed Amiche
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	anticancer drug antimicrobial peptide (AMP) dermaseptin frog skin peptides LHRH prostate cancer Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/cc2b53f64265422e8a0c096ffe5e3c9e
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spelling	oai:doaj.org-article:cc2b53f64265422e8a0c096ffe5e3c9e2021-11-11T16:47:56ZAntitumor Activity and Mechanism of Action of Hormonotoxin, an LHRH Analog Conjugated to Dermaseptin-B2, a Multifunctional Antimicrobial Peptide10.3390/ijms2221113031422-00671661-6596https://doaj.org/article/cc2b53f64265422e8a0c096ffe5e3c9e2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11303https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Prostate cancer is the most common cancer in men. For patients with advanced or metastatic prostate cancer, available treatments can slow down its progression but cannot cure it. The development of innovative drugs resulting from the exploration of biodiversity could open new therapeutic alternatives. Dermaseptin-B2, a natural multifunctional antimicrobial peptide isolated from Amazonian frog skin, has been reported to possess antitumor activity. To improve its pharmacological properties and to decrease its peripheral toxicity and lethality we developed a hormonotoxin molecule composed of dermaseptin-B2 combined with d-Lys<sup>6</sup>-LHRH to target the LHRH receptor. This hormonotoxin has a significant antiproliferative effect on the PC3 tumor cell line, with an IC50 value close to that of dermaseptin-B2. Its antitumor activity has been confirmed in vivo in a xenograft mouse model with PC3 tumors and appears to be better tolerated than dermaseptin-B2. Biophysical experiments showed that the addition of LHRH to dermaseptin-B2 did not alter its secondary structure or biological activity. The combination of different experimental approaches indicated that this hormonotoxin induces cell death by an apoptotic mechanism instead of necrosis, as observed for dermaseptin-B2. These results could explain the lower toxicity observed for this hormonotoxin compared to dermaseptin-B2 and may represent a promising targeting approach for cancer therapy.Mickael CoutyMarie DusaudMickael Miro-PadovaniLiuhui ZhangPatricia ZadigueLoussiné ZargarianOlivier LequinAlexandre de la TailleJean DelbeYamina Hamma-KourbaliMohamed AmicheMDPI AGarticleanticancer drugantimicrobial peptide (AMP)dermaseptinfrog skin peptidesLHRHprostate cancerBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11303, p 11303 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	anticancer drug antimicrobial peptide (AMP) dermaseptin frog skin peptides LHRH prostate cancer Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	anticancer drug antimicrobial peptide (AMP) dermaseptin frog skin peptides LHRH prostate cancer Biology (General) QH301-705.5 Chemistry QD1-999 Mickael Couty Marie Dusaud Mickael Miro-Padovani Liuhui Zhang Patricia Zadigue Loussiné Zargarian Olivier Lequin Alexandre de la Taille Jean Delbe Yamina Hamma-Kourbali Mohamed Amiche Antitumor Activity and Mechanism of Action of Hormonotoxin, an LHRH Analog Conjugated to Dermaseptin-B2, a Multifunctional Antimicrobial Peptide
description	Prostate cancer is the most common cancer in men. For patients with advanced or metastatic prostate cancer, available treatments can slow down its progression but cannot cure it. The development of innovative drugs resulting from the exploration of biodiversity could open new therapeutic alternatives. Dermaseptin-B2, a natural multifunctional antimicrobial peptide isolated from Amazonian frog skin, has been reported to possess antitumor activity. To improve its pharmacological properties and to decrease its peripheral toxicity and lethality we developed a hormonotoxin molecule composed of dermaseptin-B2 combined with d-Lys<sup>6</sup>-LHRH to target the LHRH receptor. This hormonotoxin has a significant antiproliferative effect on the PC3 tumor cell line, with an IC50 value close to that of dermaseptin-B2. Its antitumor activity has been confirmed in vivo in a xenograft mouse model with PC3 tumors and appears to be better tolerated than dermaseptin-B2. Biophysical experiments showed that the addition of LHRH to dermaseptin-B2 did not alter its secondary structure or biological activity. The combination of different experimental approaches indicated that this hormonotoxin induces cell death by an apoptotic mechanism instead of necrosis, as observed for dermaseptin-B2. These results could explain the lower toxicity observed for this hormonotoxin compared to dermaseptin-B2 and may represent a promising targeting approach for cancer therapy.
format	article
author	Mickael Couty Marie Dusaud Mickael Miro-Padovani Liuhui Zhang Patricia Zadigue Loussiné Zargarian Olivier Lequin Alexandre de la Taille Jean Delbe Yamina Hamma-Kourbali Mohamed Amiche
author_facet	Mickael Couty Marie Dusaud Mickael Miro-Padovani Liuhui Zhang Patricia Zadigue Loussiné Zargarian Olivier Lequin Alexandre de la Taille Jean Delbe Yamina Hamma-Kourbali Mohamed Amiche
author_sort	Mickael Couty
title	Antitumor Activity and Mechanism of Action of Hormonotoxin, an LHRH Analog Conjugated to Dermaseptin-B2, a Multifunctional Antimicrobial Peptide
title_short	Antitumor Activity and Mechanism of Action of Hormonotoxin, an LHRH Analog Conjugated to Dermaseptin-B2, a Multifunctional Antimicrobial Peptide
title_full	Antitumor Activity and Mechanism of Action of Hormonotoxin, an LHRH Analog Conjugated to Dermaseptin-B2, a Multifunctional Antimicrobial Peptide
title_fullStr	Antitumor Activity and Mechanism of Action of Hormonotoxin, an LHRH Analog Conjugated to Dermaseptin-B2, a Multifunctional Antimicrobial Peptide
title_full_unstemmed	Antitumor Activity and Mechanism of Action of Hormonotoxin, an LHRH Analog Conjugated to Dermaseptin-B2, a Multifunctional Antimicrobial Peptide
title_sort	antitumor activity and mechanism of action of hormonotoxin, an lhrh analog conjugated to dermaseptin-b2, a multifunctional antimicrobial peptide
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/cc2b53f64265422e8a0c096ffe5e3c9e
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Antitumor Activity and Mechanism of Action of Hormonotoxin, an LHRH Analog Conjugated to Dermaseptin-B2, a Multifunctional Antimicrobial Peptide

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