title: Iron chelation: inhibition of key signaling pathways in the induction of the epithelial mesenchymal transition in pancreatic cancer and other tumors.
abstract: Pancreatic cancer is the fourth leading cause of cancer-related deaths worldwide in both men and women. It presents late with non-specific symptoms, which makes it difficult to diagnose until the cancer has progressed and metastasized. Metastasis is facilitated by the epithelial-to-mes-enchymal transition (EMT), which is promoted via the oncogenic transforming growth factor beta (TGFβ), Wnt, and nuclear factor kappa B (NFκB) signaling pathways. However, recent studies have demonstrated that the EMT can be inhibited by novel anti-cancer agents known as thiosemicarbazone iron chelators. These novel agents also up-regulate the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), which can restore normal signaling to the cell and suppresses metastasis via inhibition of the EMT. Through the ability of iron chelators to up-regulate NDRG1 expression and affect multiple molecular targets, these agents have the potential to maintain the epithelial phenotype of cancer cells and may lead to improved survival rates for patients with late-stage disease.
authors.affiliation: Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Richardson
authors.forename: Zaklina
authors.initials: Z
authors.lastname: Kovacevic
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D007502:Iron Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016328:NF-kappa B / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D060449:Wnt Signaling Pathway; D018631:ras Proteins / Q000502:physiology; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007502:Iron Chelating Agents; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D018631:ras Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein