Objective: Mangafodipir exerts pharmacological effects, including vascular relaxation and protection against oxidative stress and cell death induced by oxysterols. Additionally, mangafodipir has been proposed for cardiovascular imaging. The primary metabolites of mangafodipir, manganese dipyridoxyl ethyldiamine (MnPLED) and its constituent dipyridoxyl diphosphate (Dp-dp) also known as fodipir, are pharmacologically active. However, whether they affect oxysterol-induced cytotoxicity is currently unknown. In this study, we examine whether the mangafodipir metabolite affects 7β-hydroxycholesterol (7β-OH)-induced cell death and identify the underlying mechanisms. Methods: U937 cells were pretreated or not with mangafodipir substrate (Ms; 200 µm), MnPLED (100 µmol/l) or Dp-dp (100 µmol/l) for 8 h and then exposed to 7β-OH (28 µmol/l) for 18 h. Results: Our results revealed that pretreatment with MnPLED or Dp-dp protected against 7β-OH-induced cellular reactive oxygen species (ROS) production, apoptosis, and lysosomal membrane permeabilization (LMP). MnPLED and Dp-dp, in par with Ms, confer protection against 7β-OH-induced cytotoxicity by reducing cellular ROS and stabilization of the lysosomal membrane. Conclusion: These results suggest that fodipir is the pharmacologically active part in the structure of mangafodipir, which prevents 7β-OH-induced cell death by attenuating cellular ROS and by preventing LMP. In addition, MnPLED, which is the dephosphorylated product of fodipir, exerts a similar protective effect against 7β-OH-induced cytotoxicity. This result indicates that dephosphorylation of fodipir does not affect its pharmacological actions. Altogether our result confirms the cytoprotective effect of mangafodipir and justifies its potential use as a cytoprotective adjuvant.

Keywords:
Atherosclerosis, Apoptosis, Mangafodipir, Oxidative stress , Oxysterols
1.
Ohtsuka M, Miyashita Y, Shirai K: Lipids deposited in human atheromatous lesions induce apoptosis of human vascular smooth muscle cells. J Atheroscler Thromb 2006;13:256-262.
2.
Larsson DA, Baird S, Nyhalah JD, Yuan XM, Li W: Oxysterol mixtures, in atheroma-relevant proportions, display synergistic and proapoptotic effects. Free Radic Biol Med 2006;41:902-910.
3.
Yuan XM, Li W, Brunk UT, Dalen H, Chang YH, Sevanian A: Lysosomal destabilization during macrophage damage induced by cholesterol oxidation products. Free Radic Biol Med 2000;28:208-218.
4.
Brurok H, Ardenkjaer-Larsen JH, Hansson G, Skarra S, Berg K, Karlsson JO, Laursen I, Jynge P: Manganese dipyridoxyl diphosphate: MRI contrast agent with antioxidative and cardioprotective properties? Biochem Biophys Res Commun 1999;254:768-772.
5.
Regge D, Cirillo S, Macera A, Galatola G: Mangafodipir trisodium: review of its use as an injectable contrast medium for magnetic resonance imaging. Rep Med Imaging 2009;2:55-68.
6.
Karlsson JO, Adolfsson K, Thelin B, Jynge P, Andersson RG, Falkmer UG: First clinical experience with the magnetic resonance imaging contrast agent and superoxide dismutase mimetic mangafodipir as an adjunct in cancer chemotherapy - a translational study. Transl Oncol 2012;5:32-38.
7.
Kurz T, Grant D, Andersson RG, Towart R, De Cesare M, Karlsson JO: Effects of MnDPDP and ICRF-187 on doxorubicin-induced cardiotoxicity and anticancer activity. Transl Oncol 2012;5:252-259.
8.
Alexandre J, Nicco C, Chereau C, Laurent A, Weill B, Goldwasser F, Batteux F: Improvement of the therapeutic index of anticancer drugs by the superoxide dismutase mimic mangafodipir. J Natl Cancer Inst 2006;98:236-244.
9.
Karlsson JO, Brurok H, Towart R, Jynge P: The magnetic resonance imaging contrast agent mangafodipir exerts antitumor activity via a previously described superoxide dismutase mimetic activity. Cancer Res 2006;66:598, author reply 598.
10.
Laskar A, Miah S, Andersson RG, Li W: Prevention of 7beta-hydroxycholesterol-induced cell death by mangafodipir is mediated through lysosomal and mitochondrial pathways. Eur J Pharmacol 2010;640:124-128.
11.
Karlsson JO, Brurok H, Eriksen M, Towart R, Toft KG, Moen O, Engebretsen B, Jynge P, Refsum H: Cardioprotective effects of the MR contrast agent MnDPDP and its metabolite MnPLED upon reperfusion of the ischemic porcine myocardium. Acta Radiol 2001;42:540-547.
12.
Li W, Dalen H, Eaton JW, Yuan XM: Apoptotic death of inflammatory cells in human atheroma. Arterioscler Thromb Vasc Biol 2001;21:1124-1130.
13.
Vejux A, Kahn E, Menetrier F, Montange T, Lherminier J, Riedinger JM, Lizard G: Cytotoxic oxysterols induce caspase-independent myelin figure formation and caspase-dependent polar lipid accumulation. Histochem Cell Biol 2007;127:609-624.
14.
Karlsson JO: Antioxidant activity of mangafodipir is not a new finding. J Hepatol 2004;40:872-873, author reply 873.
15.
Boya P, Kroemer G: Lysosomal membrane permeabilization in cell death. Oncogene 2008;27:6434-6451.
16.
Laskar A, Yuan XM, Li W: Dimethyl sulfoxide prevents 7beta-hydroxycholesterol-induced apoptosis by preserving lysosomes and mitochondria. J Cardiovasc Pharmacol 2010;56:263-267.
17.
Stoka V, Turk V, Turk B: Lysosomal cysteine cathepsins: signaling pathways in apoptosis. Biol Chem 2007;388:555-560.
© 2013 S. Karger AG, Basel
2013
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.