title: Targeting cancer by binding iron: Dissecting cellular signaling pathways.
abstract: Newer and more potent therapies are urgently needed to effectively treat advanced cancers that have developed resistance and metastasized. One such strategy is to target cancer cell iron metabolism, which is altered compared to normal cells and may facilitate their rapid proliferation. This is supported by studies reporting the anti-neoplastic activities of the clinically available iron chelators, desferrioxamine and deferasirox. More recently, ligands of the di-2-pyridylketone thiosemicarbazone (DpT) class have demonstrated potent and selective anti-proliferative activity across multiple cancer-types in vivo, fueling studies aimed at dissecting their molecular mechanisms of action. In the past five years alone, significant advances have been made in understanding how chelators not only modulate cellular iron metabolism, but also multiple signaling pathways implicated in tumor progression and metastasis. Herein, we discuss recent research on the targeting of iron in cancer cells, with a focus on the novel and potent DpT ligands. Several key studies have revealed that iron chelation can target the AKT, ERK, JNK, p38, STAT3, TGF-β, Wnt and autophagic pathways to subsequently inhibit cellular proliferation, the epithelial-mesenchymal transition (EMT) and metastasis. These developments emphasize that these novel therapies could be utilized clinically to effectively target cancer.
authors.affiliation: Department of Pathology and Bosch Institute, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Goldie Y L
authors.initials: GY
authors.lastname: Lui
authors.affiliation: Department of Pathology and Bosch Institute, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Zaklina
authors.initials: Z
authors.lastname: Kovacevic
authors.affiliation: Department of Pathology and Bosch Institute, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Vera
authors.initials: V
authors.lastname: Richardson
authors.affiliation: Department of Pathology and Bosch Institute, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Angelica M
authors.initials: AM
authors.lastname: Merlot
authors.affiliation: Department of Pathology and Bosch Institute, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.affiliation: Department of Pathology and Bosch Institute, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000378:metabolism* / Q000628:therapy*; D015398:Signal Transduction / Q000187:drug effects; D013882:Thiosemicarbazones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D007502:Iron Chelating Agents; D013882:Thiosemicarbazones; D007501:Iron
keywords: cancer; chelators; iron; signaling; thiosemicarbazones