The iron chelator, deferasirox, as a novel strategy for cancer treatment: oral activity against human lung tumor xenografts and molecular mechanism of action.
Deferasirox is an orally effective iron (Fe) chelator currently used for the treatment of iron-overload disease and has been implemented as an alternative to the gold standard chelator, desferrioxamine (DFO). Earlier studies demonstrated that DFO exhibits anticancer activity due to its ability to deplete cancer cells of iron. In this investigation, we examined the in vitro and in vivo activity of deferasirox against cells from human solid tumors. To date, there have been no studies to investigate the effect of deferasirox on these types of tumors in vivo. Deferasirox demonstrated similar activity at inhibiting proliferation of DMS-53 lung carcinoma and SK-N-MC neuroepithelioma cell lines compared with DFO. Furthermore, deferasirox was generally similar or slightly more effective than DFO at mobilizing cellular (59)Fe and inhibiting iron uptake from human transferrin depending on the cell type. However, deferasirox potently inhibited DMS-53 xenograft growth in nude mice when given by oral gavage, with no marked alterations in normal tissue histology. To understand the antitumor activity of deferasirox, we investigated its effect on the expression of molecules that play key roles in metastasis, cell cycle control, and apoptosis. We demonstrated that deferasirox increased expression of the metastasis suppressor protein N-myc downstream-regulated gene 1 and upregulated the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) while decreasing cyclin D1 levels. Moreover, this agent increased the expression of apoptosis markers, including cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1. Collectively, we demonstrate that deferasirox is an orally effective antitumor agent against solid tumors.
Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006 Australia.
Goldie Y L
GY
Lui
Peyman
P
Obeidy
Samuel J
SJ
Ford
Chris
C
Tselepis
Danae M
DM
Sharp
Patric J
PJ
Jansson
Danuta S
DS
Kalinowski
Zaklina
Z
Kovacevic
David B
DB
Lovejoy
Des R
DR
Richardson
D000284:Administration, Oral; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D003300:Copper / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D000077588:Deferasirox; D005260:Female; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D018241:Neuroectodermal Tumors, Primitive, Peripheral; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D015032:Zinc / Q000378:metabolism
D015703:Antigens, CD; D000970:Antineoplastic Agents; D001565:Benzoates; C068126:CD71 antigen; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007502:Iron Chelating Agents; D011990:Receptors, Transferrin; D014230:Triazoles; D019938:Cyclin D1; D003300:Copper; D007501:Iron; D017346:Protein Serine-Threonine Kinases; C491614:STK38 protein, human; D015032:Zinc; D000077588:Deferasirox