• autophagy
• autophagy inhibitor
• combination therapy
• energy metabolisms
• glutaminase inhibitor
• glutamine
• hypoxia
• iron chelator
• liver cancer
• metabolomic analysis

• Grant-in-Aid for Scientific Research (B) (16H05287) the Japan Society for the Promotion of Science
• Grant-in-Aid for Scientific Research (B) (16H05287) the Japan Society for the Promotion of Science
• Grant-in-Aid for Challenging Exploratory Research (24659369) the Japan Society for the Promotion of Science
• the Japan Society for the Promotion of Science the Japan Society for the Promotion of Science

• calcium overload
• chemotherapy
• infinite coordination polymers
• iron chelator
• ovarian cancer

• Humans
• Mice
• Animals
• Peritoneal Neoplasms/drug therapy
• Peritoneal Neoplasms/metabolism
• Peritoneal Neoplasms/pathology
• Iron/metabolism
• Reactive Oxygen Species/metabolism
• Alendronate
• Cell Line, Tumor
• Iron Chelating Agents/pharmacology

• 2018YFA0902801 National Key Research and Development Program of China
• GJHZ2072 International Collaboration Project of Chinese Academy of Sciences
• 81902426 National Natural Science Foundation of China
• 81971737 National Natural Science Foundation of China
• 2021B1212040006 Guangdong Provincial Key Laboratory of Digestive Cancer Research
• 21010500100 Technology Program
• 21JC1406002 Basic Research Program of Shanghai Municipal Government
• SGLH20181109105202075 Science and Technology Planning Project of Shenzhen Municipality
• JCYJ20210324122612032 Science and Technology Planning Project of Shenzhen Municipality
• ZSQYBRJH0001 100 Top Talents Program of Sun Yat-sen University
• National Key Research and Development Program of China
• National Natural Science Foundation of China
• Science and Technology Planning Project of Shenzhen Municipality

• acute lymphoblastic leukemia (ALL)
• acute myeloid leukemia (AML)
• iron overload
• prognosis
• transplantation

Sorafenib is used worldwide as a first-line standard systemic agent for advanced hepatocellular carcinoma (HCC) on the basis of the results of two large-scale Phase III trials. Conversely, hepatic arterial infusion chemotherapy (HAIC) is one of the most recommended treatments in Japan. Although there have been no randomized controlled trials comparing sorafenib with HAIC, several retrospective analyses have shown no significant differences in survival between the two therapies. Outcomes are favorable for HCC patients exhibiting macroscopic vascular invasion when treated with HAIC rather than sorafenib, whereas in HCC patients exhibiting extrahepatic spread or resistance to transcatheter arterial chemoembolization, good outcomes are achieved by treatment with sorafenib rather than HAIC. Additionally, sorafenib is generally used to treat patients with Child-Pugh A, while HAIC is indicated for those with either Child-Pugh A or B. Based on these findings, we reviewed treatment strategies for advanced HCC. We propose that sorafenib might be used as a first-line treatment for advanced HCC patients without macroscopic vascular invasion or Child-Pugh A, while HAIC is recommended for those with macroscopic vascular invasion or Child-Pugh A or B. Additional research is required to determine the best second-line treatment for HAIC non-responders with Child-Pugh B through future clinical trials.

• Treatment strategy
• Hepatic arterial infusion chemotherapy
• Sorafenib
• Hepatocellular carcinoma

• FDXR
• IRP1/2
• iron homeostasis
• mitochondrial iron homeostasis
• p53
• tumor suppression

To evaluate the inhibitory effects of deferasirox (DFX) against hepatocellular carcinoma (HCC) through basic and clinical studies.

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.

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%.

We demonstrated that DFX inhibited HCC in the basic study, but not in the clinical study due to dose-limiting toxicities.

• Liver tumor
• Hepatocellular carcinoma
• Advanced stage
• Iron-chelator
• Deferasirox

• Aged
• Aged, 80 and over
• Animals
• Benzoates/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Deferasirox
• Drug Screening Assays, Antitumor
• Female
• Hep G2 Cells
• Humans
• Iron Chelating Agents/therapeutic use
• Liver Neoplasms, Experimental/drug therapy
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Triazoles/therapeutic use

This work proposes a novel strategy for delivery of iron chelators to the tumour cells which is exemplified in A549 mice models by using lipidic nanocarriers and introducing biotin based targeting.