Effects of an oral iron chelator, deferasirox, on advanced hepatocellular carcinoma

Abstract

AIMTo evaluate the inhibitory effects of deferasirox (DFX) against hepatocellular carcinoma (HCC) through basic and clinical studies.METHODSIn 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.RESULTSAdministration 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%.CONCLUSIONWe demonstrated that DFX inhibited HCC in the basic study, but not in the clinical study due to dose-limiting toxicities.

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

“…We also observed increased FTH protein expression in the tissue sections of patients with cervical cancer (Figure S1 b). The increase in serum ferritin levels in patients with cervical cancer is in accordance with a previous report [28][29][30]. These results con rmed that the occurrence and development of cervical cancer is related to changes in iron metabolism.…”

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

“…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).…”

A novel, nontoxic iron chelator, super-polyphenol, effectively induces apoptosis in human cancer cell lines

“…Thus, iron chelation therapy is expected to be a novel strategy for cancer therapy and prevention, particularly oral iron chelators compared to intravenous iron chelators due to their practicability. However, iron chelators cause potentially severe side effects, which makes them difficult to use in some cancer patients [ 22 ]. One study reported that all six hepatocellular carcinoma patients treated with DFX had side effects that led to rhabdomyolysis (increased creatinine kinase activity) or anorexia.…”