Evaluation of the impact of S-adenosylmethionine-dependent methyltransferase inhibitor, 3-deazaneplanocin A, on tissue injury and cognitive function in mice
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Eva Lhuissier1, Juliette Aury-Landas1, Valentine Bouet2, Céline Bazille1,3, Yohann Repesse4,5, Thomas Freret2,6, Karim Boumédiene1 and Catherine Baugé1
1Normandie Univ, UNICAEN, BioConnecT, Caen, France
2Normandie Univ, UNICAEN, INSERM, COMETE, Caen, France
3CHU de Caen, Service d’Anatomie Pathologie, Caen, France
4Normandie Univ, UNICAEN, INSERM, EFS, PhIND, Caen, France
5CHU de Caen, Hématologie biologique, Caen, France
6Normandie Univ, UNICAEN, CURB-BRP, Caen, France
Catherine Baugé, email: [email protected]
Keywords: cognitive functions; antitumoral drug; epigenetic; toxicity
Received: December 27, 2017 Accepted: March 22, 2018 Published: April 17, 2018
Cancer patients display cognitive impairment due, at least partly, to the treatments. Additionally, chemotherapeutic treatments can lead to organ injury, limiting their use, and are likely to have negative impacts on patients’ quality of life. The aim of this study was to investigate the toxicity of 3-Deazaneplanocin A (DZNep) on several tissues and organs, as well as on cognitive functions. DZNep is an inhibitor of S-adenosylmethionine-dependent methyltransferase (in particular of the histone methyltransferase EZH2) which showed antitumoral functions in preclinical trials but whose effects on behavior and on organs (side effects) are not known.
Chronic injections of DZNep were performed intraperitoneally in male NMRI mice (2 mg/kg; i.p.; three times per week) during 8 weeks. A follow-up of body weight was assessed during all experiments. Histological analysis were performed on several organs. EZH2 expression and H3K27me3 were assayed by western-blot. Several behavioral tests were performed during treatment and 2 weeks after. A particular focus was made on spontaneous locomotor activity, cognitive functions (spontaneous alternation and recognition memory), and anxiety- and depression-related behavior. Hematological modifications were also assessed.
Chronic DZNep treatment transiently reduced animal growth. It had no effect on most organs but provoked a reversible splenomegaly, and persistent testis reduction and erythropoiesis. DZNep administration did not alter animal behavior.
In conclusion, this study is encouraging for the use of DZNep for cancer treatment. Indeed, it has no effect on animal behavior, conferring an advantageous safety, and induces irreversible side effects limited on testis which are unfortunately found in most chemotherapy treatments.
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