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Synthesis and Biochemical Study on the Effect of a Novel Gallium Complex on Tumor Cell Invasion and Matrix Metalloproteinase Activity in Vitro

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Synthesis and biochemical study on the effect of a novel gallium complex on tumor cell Invasion and matrix metalloproteinase activity in vitro. Ahmed Mohamed To cite this version: Ahmed Mohamed. Synthesis and biochemical study on the effect of a novel gallium complex on tumor cell Invasion and matrix metalloproteinase activity in vitro.. Inorganic chemistry. Université Paris Saclay (COmUE); Université Aïn-Chams (Le Caire), 2017. English. NNT : 2017SACLS108. tel-01541531 HAL Id: tel-01541531 https://tel.archives-ouvertes.fr/tel-01541531 Submitted on 19 Jun 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. NNT : 2017SACLS108 THÈSE DE DOCTORAT DE L’UNIVERSITÉ PARIS-SACLAY PRÉPARÉE À LA FACULTÉ DE PHARMACIE DE CHÂTENAY-MALABRY ÉCOLE DOCTORALE N° 569 ITFA Innovation Thérapeutique : du fondamental à l’appliqué Pharmacotechnie et biopharmacie Par Ahmed Mohamed Mohsen Synthesis and biochemical study on the effect of a novel gallium complex on tumor cell invasion and matrix metalloproteinase activity in vitro Thèse présentée et soutenue à Châtenay-Malabry, le 10 Mai 2017 : Composition du Jury : Dr, Escargueil Alexandre Maître de Conférences à l’Université P.& M. Curie Rapporteur Dr, Deschamps Patrick Maître de Conférences à l’Université Paris Descartes Rapporteur Pr, Cavé Christian Professeur à l’Université Paris-Sud Président du Jury Pr Morjani Hamid Professeur à l’Université de Reims Examinateur Dr Collery Philippe Praticien Hospitalier, Société de Coordination Thérapeutique Examinateur Dr Desmaële Didier Directeur de Recherche à l’Institut Galien Directeur de Thèse Titre : Synthèse et étude biochimique de l’effet d’un nouveau complexe du gallium sur l’invasion tumorale et l’activité inhibitrice des métalloprotéases matricielles in vitro Mots clés : gallium, complexe de coordination, agent anticancéreux, métastase, métalloprotéinase matricielle Deux complexes de gallium solubles dans l'eau d'AKT dans les cellules cancéreuses. L'activité de formule [Ga(III)LCl], où L est la forme de GS2 sur l'invasion cellulaire et sur déprotonée de dérivés d'acide N-2- l'expression et l'activité des métalloprotéinases hydroxybenzyl-aspartique ont été synthétisés et matricielles (MMP) a été étudiée en utilisant caractérisés par RMN 1H et 13C, FT-IR, une chambre de Boyden revêtue de collagène spectrométrie de masse et analyse élémentaire. de type I. Nous avons analysé l'activité sur les Les données analytiques obtenues sont MMPs par zymographie et dosage enzymatique cohérentes avec une structure mononucléaire en utilisant des substrats fluorogènes à haute dans laquelle le cation gallium (III) est ligandé affinité. Une inhibition sélective de MMP-14 a par l'un des deux groupes acide carboxylique, été observée pour bloquer la migration et l'oxygène phénolique et l’atome d'azote du l'invasion de cellules tumorales. L'expression groupe 2-hydroxybenzylamino. Dans une telle de l'ARNm des MMP a été analysée par qRT- structure, le ligand tridendate assure la liaison PCR. GS2 induit une diminution de l'invasion de l'ion métallique tandis que l'appendice cellulaire. Un effet d'inhibition dose- carboxylique fournit la solubilité dans l'eau. La dépendante a été observé sur les activités de cytotoxicité du complexe gallium de l'acide MMP-2, MMP-9 et MMP-14. Une diminution (R)-2-(5-chloro-2- de l'expression de l'ARNm de MMP-14 a été hydroxybenzylamino)succinique (GS2) a été observée dans les deux lignées cellulaires, évaluée contre les lignées cellulaires du cancer tandis que l'expression des ARNm de MMP-2 du sein humain MDA-MB231 et de et de MMP-9 ne décroit que dans les cellules fibrosarcome HT-1080. Nous avons établi que tumorales MDA-MB231. Les données GS2 est plus cytotoxique que le dérivé obtenues sur l'expression de l'ARNm de MMP- dépourvu de chlore aromatique et que le 14 ont été confirmées par analyse Western chlorure de gallium. GS2 est capable d'induire Blot. GS2 semble être une molécule capable de l'apoptose par la régulation négative de la réduire l'activité de MMP-14 dans des maladies phosphorylation de l'AKT, un arrêt du cycle métastatiques cancéreuses présentant un niveau cellulaire en G2M via l’activation de la voie élevé d'expression et d'activité de MMP-14. En des caspases 3/7. Bien que de nombreux effets conclusion, ces données montrent que le moléculaires et cellulaires du Ga aient été complexe GS2, en combinaison avec une décrits, y compris l'inhibition du protéasome et chimiothérapie cytotoxique, est un composé les activités ostéoclastiques, le complexe GS2 prometteur pour la thérapie anti-invasive et apparaît comme le premier complexe de anticancéreuse. gallium capable de réduire la phosphorylation Université Paris-Saclay Espace Technologique / Immeuble Discovery Route de l’Orme aux Merisiers RD 128 / 91190 Saint-Aubin, France Title : Synthesis and biochemical study on the effect of a novel gallium complex on tumor cell invasion and matrix metalloproteinase activity in vitro Keywords : gallium, coordination complex, anticancer agent, metastasis, matrix metalloproteinase Abstract : Two water soluble gallium decrease AKT phosphorylation in cancer cells. complexes with formula [Ga(III)LCl], where L The activity of GS2 on cell invasion and on the stands for the deprotonated form of N-2- expression and activity of Matrix hydroxybenzyl aspartic acid derivatives were Metalloproteinases (MMPs) have been synthesized and characterized by 1H NMR, 13C investigated using modified Boyden chamber NMR, FT-IR, mass spectrometry and elemental coated with type I collagen. We analyzed the analysis. The analytical data are consistent with activity on MMPs by zymography and a mononuclear structure in which the gallium enzymatic assay using high affinity fluorogenic (III) cation is liganded by one of the two substrates. A selective inhibition of MMP-14 carboxylic acid groups, the phenol oxygen and has been reported to blocks tumor cell the nitrogen atom of the 2- migration and invasion. The expression of hydroxybenzylamino group. In such a MMPs mRNA was analyzed by qRT- structure, the tridendate ligand secures the PCR. GS2 induces a decrease in cell invasion. binding of the metal ion whereas the carboxylic A dose dependent inhibition effect was appendage provides the water solubility. The observed on MMP-2, MMP-9 and MMP-14 cytotoxicity of the gallium complex of (R)-2- activities. A decrease in MMP-14 mRNA (5-chloro-2-hydroxybenzylamino) succinic expression was observed in both cell lines, acid (GS2) was evaluated against human breast whereas MMP-2 and MMP-9 mRNA carcinoma MDA-MB231 and fibrosarcoma expression was decreased only in MDA- HT-1080 cell lines. The 5-chloro derivative MB231 cells. Thus, we propose that GS2 GS2 was found to be more cytotoxic than the compound may be a potential candidate to unsubstituted derivative and GaCl3. GS2 decrease the MMP-14 activity in cancer induces apoptosis through down-regulation of metastatic diseases presenting high level of AKT phosphorylation, G2M arrest in cell cycle MMP-14 expression and activity. Taken via activation of the caspase3/7 pathway. together, these data show that GS2, in Although, many molecular and cell effects of combination with cytotoxic chemotherapy a is Ga have been described, including proteasome a promising compound for anti-invasive and inhibition and osteoclastic activities, GS2 anticancer therapy. appears as the first gallium compound able to Université Paris-Saclay Espace Technologique / Immeuble Discovery Route de l’Orme aux Merisiers RD 128 / 91190 Saint-Aubin, France Acknowledgments I gratefully acknowledge the "Institut Français d’Egypte" for the funding sources that made my Ph.D. work possible. I would like greet the French Institute of Egypt which, by supporting Egyptian researchers to come to France, gives them the opportunity to deepen the relations between the two peoples, thus allowing a better understanding between our civilizations Firstly, I would like to express my sincere gratitude to my advisor Dr. Didier Desmaële for the continuous support of my Ph.D study and related research, for his patience, motivation, and immense knowledge. His guidance helped me in all the time of research and writing of that thesis. I could not have imagined having a better advisor and mentor for my Ph.D study. Also, I am also grateful to Dr Phillipe Collery and his organization (Société de Coordination de Recherche Thérapeutique, Bastia, France) for his endless enthusiasm for metallodrugs and his material and psychological support during my Ph.D stays in France. I’d like to thank Professor Gilane Mohamed Sabry, Professor Abd Elfattah Badawi and Professor Rasha Elshrif for their co-supervision and their support into Ain Shams University. My sincere thanks also go to Professor Hamid Morjani, who helped me during my stay in Reims University. I would like to show him and his family my respect and appreciation and thank him for his hospitality. I would like to thank him about providing me the opportunity to join his team as trainee, with full access to the laboratory and research facilities. Without his precious support it would not be possible to conduct this research. Besides my advisor, I would like to thank the members of my thesis committee: Dr Patrick Deschamps and Dr Alexander Escargueil who spent time reviewing this manuscript. I wish thank Professor Christian Cavé for his encouragement. I wish thank all the members of the committee for their comments which incent me to widen my research from various perspectives. Also, I am sending all my grateful to Dr Pierre Jeannesson, Dr Roselyne Garnotel, Dr Bertrand Brassart and Dr Nicolas Etique for their help and support during fulfillment of the biological experiments.
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