The iron chelating agent, deferoxamine detoxifies Fe(Salen)-induced cytotoxicity

Masanari Umemura; Jeong-Hwan Kim; Haruki Aoyama; Yujiro Hoshino; Hidenobu Fukumura; Rina Nakakaji; Itaru Sato; Makoto Ohtake; Taisuke Akimoto; Masatoshi Narikawa; Ryo Tanaka; Takayuki Fujita; Utako Yokoyama; Masataka Taguri; Satoshi Okumura; Motohiko Sato; Haruki Eguchi; Yoshihiro Ishikawa

doi:10.1016/j.jphs.2017.07.002

Journal of Pharmacological Sciences (Aug 2017)

The iron chelating agent, deferoxamine detoxifies Fe(Salen)-induced cytotoxicity

Masanari Umemura,
Jeong-Hwan Kim,
Haruki Aoyama,
Yujiro Hoshino,
Hidenobu Fukumura,
Rina Nakakaji,
Itaru Sato,
Makoto Ohtake,
Taisuke Akimoto,
Masatoshi Narikawa,
Ryo Tanaka,
Takayuki Fujita,
Utako Yokoyama,
Masataka Taguri,
Satoshi Okumura,
Motohiko Sato,
Haruki Eguchi,
Yoshihiro Ishikawa

Affiliations

Masanari Umemura: Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Jeong-Hwan Kim: Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Haruki Aoyama: Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Yujiro Hoshino: Department of Environment and Natural Sciences, Graduate School of Environment and Information Sciences, Yokohama National University, 79-7, Tokiwada, Hodogaya, Yokohama 240-8501, Japan
Hidenobu Fukumura: Fukumura Orthopedic Clinic, 1869-1 Shimokurata, Hanatachi, Yokohama 244-0815, Japan
Rina Nakakaji: Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Itaru Sato: Sato Oral and Maxillofacial Surgery Clinic, 1-6-27 2F, Zushi, Zushi 249-0006, Japan
Makoto Ohtake: Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Taisuke Akimoto: Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Masatoshi Narikawa: Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Ryo Tanaka: Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Takayuki Fujita: Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Utako Yokoyama: Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Masataka Taguri: Department of Biostatistics, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Satoshi Okumura: Tsurumi University School of Dental Medicine, 2-1-3, Tsurumi, Yokohama 230-8501, Japan
Motohiko Sato: Department of Physiology, Aichi Medical University, 1-1, Yazakokarimata, Nagakute, Aichi 480-1103, Japan
Haruki Eguchi: Advanced Applied Science Department, Research Laboratory, IHI Corporation, Shinnakaharamachi, Isogo, Yokohama 235-8501, Japan
Yoshihiro Ishikawa: Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan

DOI: https://doi.org/10.1016/j.jphs.2017.07.002
Journal volume & issue: Vol. 134, no. 4
pp. 203 – 210

Abstract

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Iron-salen, i.e., μ-oxo-N,N′-bis(salicylidene)ethylenediamine iron (Fe(Salen)) was a recently identified as a new anti-cancer compound with intrinsic magnetic properties. Chelation therapy has been widely used in management of metallic poisoning, because an administration of agents that bind metals can prevent potential lethal effects of particular metal. In this study, we confirmed the therapeutic effect of deferoxamine mesylate (DFO) chelation against Fe(Salen) as part of the chelator antidote efficacy. DFO administration resulted in reduced cytotoxicity and ROS generation by Fe(Salen) in cancer cells. DFO (25 mg/kg) reduced the onset of Fe(Salen) (25 mg/kg)-induced acute liver and renal dysfunction. DFO (300 mg/kg) improves survival rate after systematic injection of a fatal dose of Fe(Salen) (200 mg/kg) in mice. DFO enables the use of higher Fe(Salen) doses to treat progressive states of cancer, and it also appears to decrease the acute side effects of Fe(Salen). This makes DFO a potential antidote candidate for Fe(Salen)-based cancer treatments, and this novel strategy could be widely used in minimally-invasive clinical settings.

Published in Journal of Pharmacological Sciences

ISSN: 1347-8613 (Print)
Publisher: Elsevier
Country of publisher: Japan
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: http://www.journals.elsevier.com/journal-of-pharmacological-sciences

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