The Iron Chelator, Dp44mT, Effectively Inhibits Human Oral Squamous Cell Carcinoma Cell Growth in Vitro and in Vivo

Int J Mol Sci. 2016 Aug 31;17(9):1435. doi: 10.3390/ijms17091435.

Abstract

Oral squamous cell carcinoma (OSCC) is a common malignancy with a growing worldwide incidence and prevalence. The N-myc downstream regulated gene (NDRG) family of NDRG1, 2, 3, and mammary serine protease inhibitor (Maspin) gene are well-known modulators in the neoplasia process. Current research has considered iron chelators as new anti-cancer agents; however, the anticancer activities of iron chelators and their target genes in OSCC have not been well investigated. We showed that iron chelators (Dp44mT, desferrioxamine (DFO), and deferasirox) all significantly inhibit SAS cell growth. Flow cytometry further indicated that Dp44mT inhibition of SAS cells growth was partly due to induction of G1 cell cycle arrest. Iron chelators enhanced expressions of NDRG1 and NDRG3 while repressing cyclin D1 expression in OSCC cells. The in vivo antitumor effect on OSCC and safety of Dp44mT were further confirmed through a xenograft animal model. The Dp44mT treatment also increased Maspin protein levels in SAS and OECM-1 cells. NDRG3 knockdown enhanced the growth of OECM-1 cells in vitro and in vivo. Our results indicated that NDRG3 is a tumor suppressor gene in OSCC cells, and Dp44mT could be a promising therapeutic agent for OSCC treatment.

Keywords: DFO; Maspin; NDRG1; NDRG3; deferasirox.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Iron Chelating Agents / pharmacology*
  • Iron Chelating Agents / therapeutic use
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mouth Neoplasms / drug therapy*
  • Mouth Neoplasms / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Serpins / genetics
  • Serpins / metabolism
  • Thiosemicarbazones / pharmacology*
  • Thiosemicarbazones / therapeutic use

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • Iron Chelating Agents
  • N-myc downstream-regulated gene 1 protein
  • NDRG3 protein, human
  • Nerve Tissue Proteins
  • SERPIN-B5
  • Serpins
  • Thiosemicarbazones
  • di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone
  • Cyclin D1