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

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

doi:10.1186/s12885-016-2744-9

Cited by 44 publications

(51 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DFX was effective against leukemia cells in preclinical studies and because leukemia patients receive repeated blood transfusions, DFX offers a dual benefit as an anti-cancer agent and treatment for iron overload complications. Additionally, DFO and DFX are effective in preclinical studies of pancreatic (193), breast (194), liver (183), gastric (195), and esophageal (196) cancers, and because they are well-characterized they are often used as positive controls for the study of other iron modulators. Despite promising preclinical results, a pilot study of DFX in advanced hepatocellular carcinoma patients found doselimiting toxicities and the majority (4/5) of the patient tumors progressed while on treatment, therefore the efficacy of DFX for the treatment of solid tumors remains questionable (183).…”

Section: Iron Chelationmentioning

confidence: 99%

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

et al. 2020

View full text Add to dashboard Cite

Iron is an essential nutrient that plays a complex role in cancer biology. Iron metabolism must be tightly controlled within cells. Whilst fundamental to many cellular processes and required for cell survival, excess labile iron is toxic to cells. Increased iron metabolism is associated with malignant transformation, cancer progression, drug resistance and immune evasion. Depleting intracellular iron stores, either with the use of iron chelating agents or mimicking endogenous regulation mechanisms, such as microRNAs, present attractive therapeutic opportunities, some of which are currently under clinical investigation. Alternatively, iron overload can result in a form of regulated cell death, ferroptosis, which can be activated in cancer cells presenting an alternative anti-cancer strategy. This review focuses on alterations in iron metabolism that enable cancer cells to meet metabolic demands required during different stages of tumorigenesis in relation to metastasis and immune response. The strength of current evidence is considered, gaps in knowledge are highlighted and controversies relating to the role of iron and therapeutic targeting potential are discussed. The key question we address within this review is whether iron modulation represents a useful approach for treating metastatic disease and whether it could be employed in combination with existing targeted drugs and immune-based therapies to enhance their efficacy.

show abstract

Section: Iron Chelationmentioning

confidence: 99%

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The antiproliferative activity of iron chelators was first demonstrated in leukemia in 1986 [ 17 , 18 ], and the antiproliferative activity of DFX has been investigated in various cancers [ 7 , 8 , 19 – 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, deferasirox (DFX), a new oral iron chelator, has been developed. We found that DFX has antiproliferative activity against pancreatic cancer cells in vitro and in vivo ; however, DFX did not induce apoptosis sufficiently [ 8 ]. We have also reported that the combination of DFX and sorafenib exerts a stronger inhibitory effect in hepatocarcinogenesis compared with DFX alone [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Deferasirox, an oral iron chelator, with gemcitabine synergistically inhibits pancreatic cancer cell growthin vitroandin vivo

et al. 2018

Self Cite

View full text Add to dashboard Cite

ObjectivesIron is an essential element for cell proliferation and growth processes. We have reported that deferasirox (DFX), an oral iron chelator, showed antiproliferative activity against pancreatic cancer cells. This study aimed to elucidate the effects of combination of gemcitabine (GEM), standard chemotherapy for pancreatic cancer, and DFX in vitro and in vivo.ResultsGEM+DFX showed antiproliferative activity and induced apoptosis in pancreatic cancer cells in vitro. GEM+DFX suppressed xenograft tumor growth and induced apoptosis without any serious side effects compared with control, GEM, and DFX (average tumor volume: control 697 mm3 vs GEM 372 mm3, p < 0.05; GEM 372 mm3 vs GEM+DFX 234 mm3, p < 0.05). RRM1 and RRM2 protein levels were substantially reduced by DFX in BxPC-3 in vitro.ConclusionGEM+DFX has significant anticancer effects on pancreatic cancer cell through RR activity suppression.MethodsBxPC-3, a human pancreatic cancer cell line, was used in all experiments. Cellular proliferation rate was measured using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay. Apoptosis was evaluated by flow cytometry and by measuring caspase 3/7 activity with luminescence assay. In the tumor xenografts in nude mice models, when five weeks after engraftment, drug administration began (day 0). After treatment for 21 days, the mice were sacrificed and the tumors were excised. Apoptotic cells in xenografts were evaluated by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay. Protein levels of ribonucleotide reductase (RR) subunit 1 (RRM1) and RR subunit 2 (RRM2) in BxPC-3 cells were assessed by western blot in vitro.

show abstract

“…NDRG1 is de ned as a metastasis suppressor and can be downregulated in many types of cancer, and is thought to be an indication of tumor progression in a variety of cancers [13]. The c-myc gene is ampli ed and upregulated in many human tumors and plays an important role in their malignant regulation, proliferation, and metastasis [14].…”

Section: Dfx Inhibits the Invasion Ability Of Cervical Cancer Cells Bmentioning

confidence: 99%

Deferasirox Shows Inhibition Activity Against Cervical Cancer in vitro and in vivo

Zhou

Cui

Kuang

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Iron depletion may be a novel therapeutic strategy for cancer. As an oral iron chelator, deferasirox (DFX) is expected to become an anticancer agent. This study aimed to assess the effects of DFX on cervical cancer.Methods: The effects of DFX on cellular iron metabolism, cell viability, cell cycle and apoptosis, and cell invasion were assessed in two cervical cancer cell lines. The effects of DFX on the expression of cell cycle regulators cyclin D1, cyclin E and proliferating cell nuclear antigen (PCNA) were examined. The expression of N-myc downstream regulated gene 1 (NDRG1) and c-myc, and the activation of the MEK/ERK signaling pathway were investigated. The effect of DFX on tumor burden was assessed using a murine xenograft model.Results: DFX decreased the viability of HeLa and SiHa cells, induced cell cycle and apoptosis, and decreased cell invasion. The expression of NDRG1 was upregulated while that of c-myc was downregulated. The activation of the MEK/ERK signaling pathway was inhibited by DFX. DFX also significantly suppressed xenograft tumor growth with no serious side effects, decreased ferritin levels in nude mice serum, and decreased ferritin heavy chain (FTH) expression in xenograft tumor tissue.Conclusions: The inhibitory effect of DFX on cervical cancer cells and xenograft tumor growth was related to its effective depletion of iron in tumor cells. These results demonstrate that DFX has potential as a therapeutic agent for cervical cancer.

show abstract

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

Cited by 44 publications

References 36 publications

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

Deferasirox, an oral iron chelator, with gemcitabine synergistically inhibits pancreatic cancer cell growthin vitroandin vivo

Deferasirox Shows Inhibition Activity Against Cervical Cancer in vitro and in vivo

Contact Info

Product

Resources

About