Iron Deprivation Suppresses Hepatocellular Carcinoma Growth in Experimental Studies

Abstract

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 À/À ) 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 À/À 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. Clin Cancer Res; 17(24); 7625-33. Ó2011 AACR.

Deferasirox shows in vitro and in vivo antileukemic effects on murine leukemic cell lines regardless of iron status

“…These inhibitory effects of DFO and DFX on L1210 leukemia cells were closely related to apoptosis, because the effects of DFO and DFX on viability of L1210 leukemia cells showed a similar trend to that of the apoptosis-inducing activity of DFO and DFX on L1210 leukemia cells. In this study, the apoptotic effects of DFO and DFX on L1210 leukemia cells agree with the results of other studies indicating that ICAs induce apoptosis in rapid proliferating cells such as myeloid leukemia cells, and hepatoma cells [9][10][11][12]. Our study showed that the ICA-mediated apoptosis of L1210 leukemia cells was not associated with the Fas/FasL pathway.…”

“…Previous studies have shown that iron supplementation can partially or completely reverse the inhibitory effects of ICAs on various cells [5,6,9,10]. Ferric iron was reported to be less effective in restoring the viability of tumor cells than ferrous iron [19,20].…”

“…As a result, rapidly proliferating cells, such as cancer cells, have a higher requirement for iron and are highly vulnerable to iron depletion by ICAs. Various ICAs have been investigated for their anticancer activity in cell culture experiments, animal models, and human clinical trials [5][6][7][8][9].…”

“…Various studies have shown the in vitro and in vivo antiproliferative activity of DFO against a wide range of tumors, including hepatomas, leukemias, and neuroblastomas [5][6][7]9]. However, the high hydrophilicity and short half-life of DFO limits its duration and the choice for its route of administration [2][3][4].…”

Quinoline based mono- and bis-(thio)carbohydrazones: synthesis, anticancer activity in 2D and 3D cancer and cancer stem cell models

“…[35][36][37][38][39][40] Here, we present results of the rst systematically organized investigation of antitumor activity of three mono-carbohydrazones and three mono-thiocarbohydrazones with their corresponding bisstructural counterparts. Despite the development of new therapeutics with increasing success in treating malignancies, recurrence of disease can develop years aer efficient therapy.…”