TY - JOUR
T1 - Iron deprivation suppresses hepatocellular carcinoma growth in experimental studies
AU - Ba, Qian
AU - Hao, Miao
AU - Huang, He
AU - Hou, Junmei
AU - Ge, Shichao
AU - Zhang, Zhuzhen
AU - Yin, Jun
AU - Chu, Ruiai
AU - Jiang, Hualiang
AU - Wang, Fudi
AU - Chen, Kaixian
AU - Liu, Hong
AU - Wang, Hui
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2011/12/15
Y1 - 2011/12/15
N2 - Purpose: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, and iron overload is a significant risk factor in the development of HCC. In this study, we investigated the potential application of depriving iron by a novel iron chelator, thiosemicarbazone-24 (TSC24), in HCC treatment. Experimental Design: Two HCC cell lines and HFE knockout (HFE-/-) mice were used to determine iron chelation efficiency of TSC24. The anticancer effects of TSC24 on HCC were analyzed in vitro and in athymic xenograft mouse models. Results: Treatment with TSC24 significantly decreased the cellular iron concentration in hepatoma cells and the serum iron concentration in HFE -/- mice by blocking iron uptake and interfering with normal regulation of iron levels. Moreover, the viability of HCC cell lines was reduced by TSC24. Confirming the mechanism of the agent, this decrease in viability could be partially rescued by addition of exogenous iron. TSC24 also suppressed tumor growth in athymic mice bearing human HCC xenografts in a concentration-dependent manner, without apparent toxicity in parallel with a decrease in the serum iron level. Further studies revealed that TSC24 efficiently triggered cell-cycle arrest and apoptosis in Hep3B and HepG2 cell lines. Conclusions: TSC24 is a potent iron chelator that suppresses human HCC tumor growth by disrupting iron homeostasis, reducing available iron, and triggering cell-cycle arrest and apoptosis, without apparent host toxicity at effective doses. Thus, TSC24 shows great potential for the treatment of HCC.
AB - Purpose: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, and iron overload is a significant risk factor in the development of HCC. In this study, we investigated the potential application of depriving iron by a novel iron chelator, thiosemicarbazone-24 (TSC24), in HCC treatment. Experimental Design: Two HCC cell lines and HFE knockout (HFE-/-) mice were used to determine iron chelation efficiency of TSC24. The anticancer effects of TSC24 on HCC were analyzed in vitro and in athymic xenograft mouse models. Results: Treatment with TSC24 significantly decreased the cellular iron concentration in hepatoma cells and the serum iron concentration in HFE -/- mice by blocking iron uptake and interfering with normal regulation of iron levels. Moreover, the viability of HCC cell lines was reduced by TSC24. Confirming the mechanism of the agent, this decrease in viability could be partially rescued by addition of exogenous iron. TSC24 also suppressed tumor growth in athymic mice bearing human HCC xenografts in a concentration-dependent manner, without apparent toxicity in parallel with a decrease in the serum iron level. Further studies revealed that TSC24 efficiently triggered cell-cycle arrest and apoptosis in Hep3B and HepG2 cell lines. Conclusions: TSC24 is a potent iron chelator that suppresses human HCC tumor growth by disrupting iron homeostasis, reducing available iron, and triggering cell-cycle arrest and apoptosis, without apparent host toxicity at effective doses. Thus, TSC24 shows great potential for the treatment of HCC.
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U2 - 10.1158/1078-0432.CCR-10-3099
DO - 10.1158/1078-0432.CCR-10-3099
M3 - Article
C2 - 22052937
AN - SCOPUS:84055222075
SN - 1078-0432
VL - 17
SP - 7625
EP - 7633
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -