Copyright
©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
Effects of an oral iron chelator, deferasirox, on advanced hepatocellular carcinoma
Issei Saeki, Naoki Yamamoto, Takahiro Yamasaki, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Koichi Uchida, Kenji Tani, Isao Sakaida
Issei Saeki, Naoki Yamamoto, Taro Takami, Masaki Maeda, Koichi Fujisawa, Takuya Iwamoto, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
Naoki Yamamoto, Yamaguchi University Health Administration Center, Yamaguchi 753-8511, Japan
Takahiro Yamasaki, Toshihiko Matsumoto, Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
Koichi Uchida, Department of Human Nutrition Faculty of Nursing and Human Nutrition, Yamaguchi Prefectural University, Yamaguchi 753-8502, Japan
Koichi Fujisawa, Center of Research and Education for Regenerative Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
Kenji Tani, Department of Veterinary Surgery, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi 753-8511, Japan
Author contributions: Saeki I and Yamamoto N contributed equally to this work; Saeki I, Yamamoto N and Yamasaki T analyzed the data; Saeki I, Yamamoto N and Yamasaki T wrote the paper; Saeki I, Yamasaki T, Iwamoto T, Hidaka I, Ishikawa T and Uchida K performed the clinical experiments; Yamamoto N, Takami T, Maeda M, Fujisawa K, Matsumoto T and Tani K performed the basic experiments; Tani K and Sakaida I contributed reagents/materials/analysis tools.
Supported by Grants-in-Aid for Scientific Research from the Japan Society for the Program of Science, No. 23590978 and No. 16H05287; the Strategic Research Promotion Program from Yamaguchi University.
Institutional review board statement: This study (H25-148) was approved by the Institutional Review Board of Yamaguchi University Hospital. The study protocol was designed according to the principles of the 1975 Declaration of Helsinki.
Clinical trial registration statement: This study is single arm, non-randomized, open-labeled study. The trial was registered online (http://www.umin.ac.jp/) (UMIN 000013451).
Informed consent statement: Written informed consent was obtained from all patients prior to enrollment.
Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Takahiro Yamasaki, MD, PhD, Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi, Ube, Yamaguchi 755-8505, Japan. t.yama@yamaguchi-u.ac.jp
Telephone: +81-836-222336 Fax: +81-836-222338
Received: June 28, 2016
Peer-review started: June 29, 2016
First decision: August 19, 2016
Revised: September 6, 2016
Accepted: September 28, 2016
Article in press: September 28, 2016
Published online: October 28, 2016
Processing time: 120 Days and 5.8 Hours
AIM
To evaluate the inhibitory effects of deferasirox (DFX) against hepatocellular carcinoma (HCC) through basic and clinical studies.
METHODS
In the basic study, the effect of DFX was investigated in three hepatoma cell lines (HepG2, Hep3B, and Huh7), as well as in an N-nitrosodiethylamine-induced murine HCC model. In the clinical study, six advanced HCC patients refractory to chemotherapy were enrolled. The initial dose of DFX was 10 mg/kg per day and was increased by 10 mg/kg per day every week, until the maximum dose of 30 mg/kg per day. The duration of a single course of DFX therapy was 28 consecutive days. In the event of dose-limiting toxicity (according to the Common Terminology Criteria for Adverse Events v.4.0), DFX dose was reduced.
RESULTS
Administration of DFX inhibited the proliferation of hepatoma cell lines and induced the activation of caspase-3 in a dose-dependent manner in vitro. In the murine model, DFX treatment significantly suppressed the development of liver tumors (P < 0.01), and significantly upregulated the mRNA expression levels of hepcidin (P < 0.05), transferrin receptor 1 (P < 0.05), and hypoxia inducible factor-1α (P < 0.05) in both tumor and non-tumor tissues, compared with control mice. In the clinical study, anorexia and elevated serum creatinine were observed in four and all six patients, respectively. However, reduction in DFX dose led to decrease in serum creatinine levels in all patients. After the first course of DFX, one patient discontinued the therapy. We assessed the tumor response in the remaining five patients; one patient exhibited stable disease, while four patients exhibited progressive disease. The one-year survival rate of the six patients was 17%.
CONCLUSION
We demonstrated that DFX inhibited HCC in the basic study, but not in the clinical study due to dose-limiting toxicities.
Core tip: There are currently no established second-line chemotherapies for advanced hepatocellular carcinoma (HCC) patients. Iron chelators exert antiproliferative effects in several cancers. We demonstrated the inhibition of HCC by deferasirox (DFX) in the basic study. However, the efficacy of DFX in our clinical study could not be verified due to dose-limiting toxicities. Although iron chelators have promising therapeutic potential, further examinations are necessary to establish their clinical applications.
