Strengthening Anti-Glioblastoma Effect by Multi-Branched Dendrimers Design of a Scorpion Venom Tetrapeptide
Wassim Moslah,
Dorra Aissaoui-Zid,
Soioulata Aboudou,
Zaineb Abdelkafi-Koubaa,
Marie Potier-Cartereau,
Aude Lemettre,
Ines ELBini-Dhouib,
Naziha Marrakchi,
Didier Gigmes,
Christophe Vandier,
José Luis,
Kamel Mabrouk,
Najet Srairi-Abid
Affiliations
Wassim Moslah
Laboratoire des Biomolécules, Venins et Applications Théranostiques (LBVAT), LR20IPT01, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis 1002, Tunisia
Dorra Aissaoui-Zid
Laboratoire des Biomolécules, Venins et Applications Théranostiques (LBVAT), LR20IPT01, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis 1002, Tunisia
Soioulata Aboudou
Institut de Chimie Radicalaire (ICR), Aix-Marseille Université, CNRS, ICR UMR 7273, 13397 Marseille, France
Zaineb Abdelkafi-Koubaa
Laboratoire des Biomolécules, Venins et Applications Théranostiques (LBVAT), LR20IPT01, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis 1002, Tunisia
Marie Potier-Cartereau
N2C UMR 1069, INSERM, Faculté des Sciences et Techniques, Université de Tours, 37032 Tours, France
Aude Lemettre
N2C UMR 1069, INSERM, Faculté des Sciences et Techniques, Université de Tours, 37032 Tours, France
Ines ELBini-Dhouib
Laboratoire des Biomolécules, Venins et Applications Théranostiques (LBVAT), LR20IPT01, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis 1002, Tunisia
Naziha Marrakchi
Laboratoire des Biomolécules, Venins et Applications Théranostiques (LBVAT), LR20IPT01, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis 1002, Tunisia
Didier Gigmes
Institut de Chimie Radicalaire (ICR), Aix-Marseille Université, CNRS, ICR UMR 7273, 13397 Marseille, France
Christophe Vandier
N2C UMR 1069, INSERM, Faculté des Sciences et Techniques, Université de Tours, 37032 Tours, France
José Luis
Institut de Neurophysiopathologie (INP), UMR 7051-CNRS, Faculté de Médecine, Aix-Marseille Université, 27 bd Jean Moulin, 13385 Marseille, France
Kamel Mabrouk
Institut de Chimie Radicalaire (ICR), Aix-Marseille Université, CNRS, ICR UMR 7273, 13397 Marseille, France
Najet Srairi-Abid
Laboratoire des Biomolécules, Venins et Applications Théranostiques (LBVAT), LR20IPT01, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis 1002, Tunisia
Glioblastoma is the most aggressive and invasive form of central nervous system tumors due to the complexity of the intracellular mechanisms and molecular alterations involved in its progression. Unfortunately, current therapies are unable to stop its neoplastic development. In this context, we previously identified and characterized AaTs-1, a tetrapeptide (IWKS) from Androctonus autralis scorpion venom, which displayed an anti-proliferative effect against U87 cells with an IC50 value of 0.57 mM. This peptide affects the MAPK pathway, enhancing the expression of p53 and altering the cytosolic calcium concentration balance, likely via FPRL-1 receptor modulation. In this work, we designed and synthesized new dendrimers multi-branched molecules based on the sequence of AaTs-1 and showed that the di-branched (AaTs-1-2B), tetra-branched (AaTs-1-4B) and octo-branched (AaTs-1-8B) dendrimers displayed 10- to 25-fold higher effects on the proliferation of U87 cells than AaTs-1. We also found that the effects of the newly designed molecules are mediated by the enhancement of the ERK1/2 and AKT phosphorylated forms and by the increase in p53 expression. Unlike AaTs-1, AaTs-1-8B and especially AaTs-1-4B affected the migration of the U87 cells. Thus, the multi-branched peptide synthesis strategy allowed us to make molecules more active than the linear peptide against the proliferation of U87 glioblastoma cells.