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

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 mm(3) for controls vs. 327 mm(3) for 160 mg/kg DFX, p <0.05; average tumor volumes of 674 mm(3) for controls vs. 274 mm(3) 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.

• Authors: Hirofumi Harima, Seiji Kaino, Taro Takami, Shuhei Shinoda, Toshihiko Matsumoto, Koichi Fujisawa, Naoki Yamamoto, Takahiro Yamasaki, Isao Sakaida
• Journal: BMC cancer (BMC Cancer) Vol. 16 Pg. 702 (08 31 2016) ISSN: 1471-2407 [Electronic] England
• PMID: 27582255 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzoates
• Iron Chelating Agents
• Triazoles
• Deferasirox

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzoates (pharmacology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Deferasirox
• Flow Cytometry
• Humans
• Immunohistochemistry
• Iron Chelating Agents (pharmacology)
• Mice
• Mice, Nude
• Oligonucleotide Array Sequence Analysis
• Pancreatic Neoplasms (pathology)
• Triazoles (pharmacology)
• Xenograft Model Antitumor Assays