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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo

Authors: Hirofumi Harima, Seiji Kaino, Taro Takami, Shuhei Shinoda, Toshihiko Matsumoto, Koichi Fujisawa, Naoki Yamamoto, Takahiro Yamasaki, Isao Sakaida

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

Iron is essential for cell replication, metabolism and growth. Because neoplastic cells have high iron requirements due to their rapid proliferation, iron depletion may be a novel therapeutic strategy for cancer. Deferasirox (DFX), a novel oral iron chelator, has been successful in clinical trials in iron-overload patients and has been expected to become an anticancer agent. However, no studies have investigated the effects of DFX on pancreatic cancer. This study aimed to elucidate the effects of DFX against pancreatic cancer.

Methods

The effects of DFX on cell cycle, proliferation, and apoptosis were examined in three human pancreatic cancer cell lines: BxPC-3, HPAF-II, and Panc 10.05. The effect of orally administered DFX on the growth of BxPC-3 pancreatic cancer xenografts was also examined in nude mice. Additionally, microarray analysis was performed using tumors excised from xenografts.

Results

DFX inhibited pancreatic cancer cell proliferation in a dose-dependent manner. A concentration of 10 μM DFX arrested the cell cycle in S phase, whereas 50 and 100 μM DFX induced apoptosis. In nude mice, orally administered DFX at 160 and 200 mg/kg suppressed xenograft tumor growth with no serious side effects (n = 5; average tumor volumes of 674 mm3 for controls vs. 327 mm3 for 160 mg/kg DFX, p <0.05; average tumor volumes of 674 mm3 for controls vs. 274 mm3 for 200 mg/kg DFX, p <0.05). Importantly, serum biochemistry analysis indicated that serum levels of ferritin were significantly decreased by the oral administration of 160 or 200 mg/kg DFX (n = 5; average serum ferritin of 18 ng/ml for controls vs. 9 ng/ml for 160 mg/kg DFX, p <0.05; average serum ferritin of 18 ng/ml for controls vs. 10 ng/ml for 200 mg/kg DFX, p <0.05). Gene expression analysis revealed that most genes in pancreatic adenocarcinoma signaling, especially transforming growth factor-ß1 (TGF-ß1), were downregulated by DFX.

Conclusions

DFX has potential as a therapeutic agent for pancreatic cancer. Iron depletion was essential for the antiproliferative effect of DFX in a preclinical model, and DFX acted through the suppression of TGF-ß signaling.
Literature
1.
Egawa S, Toma H, Ohigashi H, Okusaka T, Nakao A, Hatori T, et al. Japan pancreatic cancer registry; 30th year anniversary: Japan Pancreas Society. Pancreas. 2012;41:985–92.CrossRefPubMed
2.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.CrossRefPubMed
3.
Magee CJ, Ghaneh P, Neoptolemos JP. Surgical and medical therapy for pancreatic carcinoma. Best Pract Res Clin Gastroenterol. 2002;16:435–55.CrossRefPubMed
4.
5.
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology, pancreatic adenocarcinoma. National Comprehensive Cancer Network. 2015. https://​www.​nccn.​org/​. Accessed 3 June 2015.
6.
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.CrossRefPubMed
7.
Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011;29:4548–54.CrossRef
8.
Crichton R. Iron metabolism: from molecular mechanisms to clinical consequences. Hoboken: Wiley; 2009.CrossRef
9.
Yu Y, Wong J, Lovejoy DB, Kalinowski DS, Richardson DR. Chelators at the cancer coalface: desferrioxamine to Triapine and beyond. Clin Cancer Res. 2006;12:6876–83.CrossRefPubMed
10.
Kicic A, Chua AC, Baker E. Effect of iron chelators on proliferation and iron uptake in hepatoma cells. Cancer. 2001;92:3093–110.CrossRefPubMed
11.
Yu Y, Gutierrez E, Kovacevic Z, Saletta F, Obeidy P, Suryo Rahmanto Y, et al. Iron chelators for the treatment of cancer. Curr Med Chem. 2012;19:2689–702.CrossRefPubMed
12.
13.
Sakaida I, Hironaka K, Uchida K, Okita K. Iron chelator deferoxamine reduces preneoplastic lesions in liver induced by choline-deficient L-amino acid-defined diet in rats. Dig Dis Sci. 1999;44:560–9.CrossRefPubMed
14.
Yamasaki T, Terai S, Sakaida I. Deferoxamine for advanced hepatocellular carcinoma. N Engl J Med. 2011;365:576–8.CrossRefPubMed
15.
Kovacevic Z, Chikhani S, Lovejoy DB, Richardson DR. Novel thiosemicarbazone iron chelators induce up-regulation and phosphorylation of the metastasis suppressor N-myc down-stream regulated gene 1: a new strategy for the treatment of pancreatic cancer. Mol Pharmacol. 2011;80:598–609.CrossRefPubMed
16.
Cappellini MD, Taher A. Deferasirox (Exjade) for the treatment of iron overload. Acta Haematol. 2009;122:165–73.CrossRefPubMed
17.
Bedford MR, Ford SJ, Horniblow RD, Iqbal TH, Tselepis C. Iron chelation in the treatment of cancer: a new role for deferasirox? J Clin Pharmacol. 2013;53:885–91.CrossRefPubMed
18.
Boult J, Roberts K, Brookes MJ, Hughes S, Bury JP, Cross SS, et al. Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma. Clin Cancer Res. 2008;14:379–87.CrossRefPubMed
19.
Di Martino E, Wild CP, Rotimi O, Darnton JS, Olliver RJ, Hardie LJ. IGFBP-3 and IGFBP-10 (CYR61) up-regulation during the development of Barrett’s oesophagus and associated oesophageal adenocarcinoma: potential biomarkers of disease risk. Biomarkers. 2006;11:547–61.CrossRefPubMed
20.
Bolstad BM, Irizarry RA, Astrand M, Speed TP. A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. BioInformatics. 2003;19:185–93.CrossRefPubMed
21.
Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 2004;5:R80.CrossRefPubMedPubMedCentral
22.
Ford SJ, Obeidy P, Lovejoy DB, Bedford M, Nichols L, Chadwick C, et al. Deferasirox (ICL670A) effectively inhibits oesophageal cancer growth in vitro and in vivo. Br J Pharmacol. 2013;168:1316–28.CrossRefPubMedPubMedCentral
23.
Lui GY, Obeidy P, Ford SJ, Tselepis C, Sharp DM, Jansson PJ, et al. The iron chelator, deferasirox, as a novel strategy for cancer treatment: oral activity against human lung tumor xenografts and molecular mechanism of action. Mol Pharmacol. 2013;83:179–90.CrossRefPubMed
24.
Kontoghiorghes GJ, Piga A, Hoffbrand AV. Cytotoxic and DNA-inhibitory effects of iron chelators on human leukaemic cell lines. Hematol Oncol. 1986;4:195–204.CrossRefPubMed
25.
Estrov Z, Tawa A, Wang XH, Dubé ID, Sulh H, Cohen A, et al. In vitro and in vivo effects of deferoxamine in neonatal acute leukemia. Blood. 1987;69:757–61.PubMed
26.
Brard L, Granai CO, Swamy N. Iron chelators deferoxamine and diethylenetriamine pentaacetic acid induce apoptosis in ovarian carcinoma. Gynecol Oncol. 2006;100:116–27.CrossRefPubMed
27.
Hoke EM, Maylock CA, Shacter E. Desferal inhibits breast tumor growth and does not interfere with the tumoricidal activity of doxorubicin. Free Radic Biol Med. 2005;39:403–11.CrossRefPubMed
28.
Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood. 1997;89:739–61.PubMed
29.
Lescoat G, Chantrel-Groussard K, Pasdeloup N, Nick H, Brissot P, Gaboriau F. Antiproliferative and apoptotic effects in rat and human hepatoma cell cultures of the orally active iron chelator ICL670 compared to CP20: a possible relationship with polyamine metabolism. Cell Prolif. 2007;40:755–67.CrossRefPubMed
30.
Ohyashiki JH, Kobayashi C, Hamamura R, Okabe S, Tauchi T, Ohyashiki K. The oral iron chelator deferasirox represses signaling through the mTOR in myeloid leukemia cells by enhancing expression of REDD1. Cancer Sci. 2009;100:970–7.CrossRefPubMed
31.
Jin H, Xu Z, Li D, Huang J. Antiproliferative activity and therapeutic implications of potassium tris(4-methyl-1-pyrazolyl) borohydride in hepatocellular carcinoma. Chem Biol Interact. 2014;213:69–76.CrossRefPubMed
32.
Yu Y, Kovacevic Z, Richardson DR. Tuning cell cycle regulation with an iron key. Cell Cycle. 2007;6:1982–94.CrossRefPubMed
33.
Nisbet-Brown E, Olivieri NF, Giardina PJ, Grady RW, Neufeld EJ, Séchaud R, et al. Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2003;361:1597–602.CrossRefPubMed
34.
Friess H, Yamanaka Y, Büchler M, Ebert M, Beger HG, Gold LI, et al. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterol. 1993;105:1846–56.CrossRef
35.
Yin T, Wang C, Liu T, Zhao G, Zhou F. Implication of EMT induced by TGF-beta1 in pancreatic cancer. J Huazhong Univ Sci Technolog Med Sci. 2006;26:700–2.CrossRefPubMed
36.
Ellenrieder V, Hendler SF, Boeck W, Seufferlein T, Menke A, Ruhland C, et al. Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res. 2001;61:4222–8.PubMed
37.
Lou C, Zhang F, Yang M, Zhao J, Zeng W, Fang X, et al. Naringenin decreases invasiveness and metastasis by inhibiting TGF-β-induced epithelial to mesenchymal transition in pancreatic cancer cells. PLoS ONE. 2012;7:e50956.CrossRefPubMedPubMedCentral
38.
Lui GY, Kovacevic Z, Richardson V, Merlot AM, Kalinowski DS, Richardson DR. Targeting cancer by binding iron: dissecting cellular signaling pathways. Oncotarget. 2015;6:18748–79.CrossRefPubMedPubMedCentral
Metadata
Title
Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo
Authors
Hirofumi Harima
Seiji Kaino
Taro Takami
Shuhei Shinoda
Toshihiko Matsumoto
Koichi Fujisawa
Naoki Yamamoto
Takahiro Yamasaki
Isao Sakaida
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2744-9

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