A New Manganese Superoxide Dismutase Mimetic Improves Oxaliplatin-Induced Neuropathy and Global Tolerance in Mice

Autor: Caroline Prieux-Klotz, Henri Chédotal, Martha Zoumpoulaki, Sandrine Chouzenoux, Charlotte Chêne, Alvaro Lopez-Sanchez, Marine Thomas, Priya Ranjan Sahoo, Clotilde Policar, Frédéric Batteux, Hélène C. Bertrand, Carole Nicco, Romain Coriat
Přispěvatelé: Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Sorbonne Université (SU), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Policar, Clotilde
Rok vydání: 2022
Předmět:
[CHIM.INOR] Chemical Sciences/Inorganic chemistry
colorectal cancer
Antineoplastic Agents
[CHIM.INOR]Chemical Sciences/Inorganic chemistry
Catalysis
superoxide dismutase mimetic
Inorganic Chemistry
Mice
Pt(IV) prodrugs
Superoxides
Animals
[CHIM.COOR]Chemical Sciences/Coordination chemistry
Physical and Theoretical Chemistry
Molecular Biology
Spectroscopy
Mice
Inbred BALB C
oxaliplatin-induced peripheral neuropathy
[CHIM.ORGA]Chemical Sciences/Organic chemistry
Superoxide Dismutase
Organic Chemistry
Peripheral Nervous System Diseases
Hydrogen Peroxide
General Medicine
[CHIM.COOR] Chemical Sciences/Coordination chemistry
[CHIM.ORGA] Chemical Sciences/Organic chemistry
Computer Science Applications
Oxaliplatin
[CHIM.OTHE] Chemical Sciences/Other
[CHIM.OTHE]Chemical Sciences/Other
Reactive Oxygen Species
Zdroj: International Journal of Molecular Sciences; Volume 23; Issue 21; Pages: 12938
International Journal of Molecular Sciences
International Journal of Molecular Sciences, 2022, 23 (21), pp.12938. ⟨10.3390/ijms232112938⟩
ISSN: 1422-0067
1661-6596
DOI: 10.3390/ijms232112938
Popis: International audience; Reactive oxygen species (ROS) are produced by every aerobic cell during mitochondrial oxidative metabolism as well as in cellular response to xenobiotics, cytokines, and bacterial invasion. Superoxide Dismutases (SOD) are antioxidant proteins that convert superoxide anions (O 2 •−) to hydrogen peroxide (H 2 O 2) and dioxygen. Using the differential in the level of oxidative stress between normal and cancer cells, SOD mimetics can show an antitumoral effect and prevent oxaliplatininduced peripheral neuropathy. New Pt(IV) conjugate prodrugs (OxPt-x-Mn1C1A (x = 1, 1-OH, 2)), combining oxaliplatin and a Mn SOD mimic (MnSODm Mn1C1A) with a covalent link, were designed. Their stability in buffer and in the presence of sodium ascorbate was studied. In vitro, their antitumoral activity was assessed by the viability and ROS production of tumor cell lines (CT16, HCT 116, KC) and fibroblasts (primary culture and NIH 3T3). In vivo, a murine model of colorectal cancer was created with subcutaneous injection of CT26 cells in Balb/c mice. Tumor size and volume were measured weekly in four groups: vehicle, oxaliplatin, and oxaliplatin associated with MnSODm Mn1C1A and the bis-conjugate OxPt-2-Mn1C1A. Oxaliplatin-induced peripheral neuropathy (OIPN) was assessed using a Von Frey test reflecting chronic hypoalgesia. Tolerance to treatment was assessed with a clinical score including four items: weight loss, weariness, alopecia, and diarrhea. In vitro, Mn1C1A associated with oxaliplatin and Pt(IV) conjugates treatment induced significantly higher production of H 2 O 2 in all cell lines and showed a significant improvement of the antitumoral efficacy compared to oxaliplatin alone. In vivo, the association of Mn1C1A to oxaliplatin did not decrease its antitumoral activity, while OxPt-2-Mn1C1A had lower antitumoral activity than oxaliplatin alone. Mn1C1A associated with oxaliplatin significantly decreased OIPN and also improved global clinical tolerance of oxaliplatin. A neuroprotective effect was observed, associated with a significantly improved tolerance to oxaliplatin without impairing its antitumoral activity.
Databáze: OpenAIRE
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