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

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

J Pharmacol Sci. 2017 Aug;134(4):203-210. doi: 10.1016/j.jphs.2017.07.002. Epub 2017 Jul 25.

Authors

Masanari Umemura¹, Jeong-Hwan Kim², Haruki Aoyama³, Yujiro Hoshino⁴, Hidenobu Fukumura⁵, Rina Nakakaji⁶, Itaru Sato⁷, Makoto Ohtake⁸, Taisuke Akimoto⁹, Masatoshi Narikawa¹⁰, Ryo Tanaka¹¹, Takayuki Fujita¹², Utako Yokoyama¹³, Masataka Taguri¹⁴, Satoshi Okumura¹⁵, Motohiko Sato¹⁶, Haruki Eguchi¹⁷, Yoshihiro Ishikawa¹⁸

Affiliations

¹ Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address: [email protected].
² Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address: [email protected].
³ Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address: [email protected].
⁴ Department of Environment and Natural Sciences, Graduate School of Environment and Information Sciences, Yokohama National University, 79-7, Tokiwada, Hodogaya, Yokohama 240-8501, Japan. Electronic address: [email protected].
⁵ Fukumura Orthopedic Clinic, 1869-1 Shimokurata, Hanatachi, Yokohama 244-0815, Japan. Electronic address: [email protected].
⁶ Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; Department of Oral and Maxillofacial Surgery, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address: [email protected].
⁷ Sato Oral and Maxillofacial Surgery Clinic, 1-6-27 2F, Zushi, Zushi 249-0006, Japan. Electronic address: [email protected].
⁸ Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; Department of Neurosurgery, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address: [email protected].
⁹ Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; Department of Neurosurgery, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address: [email protected].
¹⁰ Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address: [email protected].
¹¹ Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address: [email protected].
¹² Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address: [email protected].
¹³ Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address: [email protected].
¹⁴ Department of Biostatistics, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address: [email protected].
¹⁵ Tsurumi University School of Dental Medicine, 2-1-3, Tsurumi, Yokohama 230-8501, Japan. Electronic address: [email protected].
¹⁶ Department of Physiology, Aichi Medical University, 1-1, Yazakokarimata, Nagakute, Aichi 480-1103, Japan. Electronic address: [email protected].
¹⁷ Advanced Applied Science Department, Research Laboratory, IHI Corporation, Shinnakaharamachi, Isogo, Yokohama 235-8501, Japan. Electronic address: [email protected].
¹⁸ Cardiovascular Research Institute, Yokohama City University, Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address: [email protected].

PMID: 28779994
DOI: 10.1016/j.jphs.2017.07.002

Abstract

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.

Keywords: Anti-cancer; Antidote; Chelate; Deferoxamine (DFO); Fe(Salen).

MeSH terms

Acute Kidney Injury / chemically induced
Animals
Antidotes*
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / adverse effects*
Antineoplastic Agents / toxicity*
Chelating Agents / administration & dosage
Chelating Agents / adverse effects*
Chelating Agents / toxicity*
Chemical and Drug Induced Liver Injury / etiology
Deferoxamine / pharmacology*
Deferoxamine / therapeutic use*
Dose-Response Relationship, Drug
Ethylenediamines / administration & dosage
Ethylenediamines / adverse effects*
Ethylenediamines / toxicity*
Humans
Iron / administration & dosage
Iron / adverse effects*
Iron / toxicity*
Iron Chelating Agents / pharmacology*
Iron Chelating Agents / therapeutic use*
Rabbits
Reactive Oxygen Species / metabolism
Tumor Cells, Cultured

Substances

Antidotes
Antineoplastic Agents
Chelating Agents
Ethylenediamines
Iron Chelating Agents
Reactive Oxygen Species
disalicylaldehyde ethylenediamine
Iron
Deferoxamine