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

Jehn-Chuan Lee,Kun-Chun Chiang,Tsui-Hsia Feng,Sung-Ting Chuang,Horng-Heng Juang,Ke-Hung Tsui,Yu-Jen Chen,Li-Chuan Chung

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.

Highlights

Oral squamous cell carcinoma (OSCC) accounts for 90% of all oral cancers, which are the most commonly diagnosed malignancies, estimated at over 300,000 new cases annually around the world [1,2]
We further evaluated the effects of iron chelators on NDRG2, NDRG3, and mammary serine protease inhibitor (Maspin) expressions in OSCC cells
One recent study showed that Dp44mT inhibited the invasion and metastasis in hepatocellular carcinoma cells by increasing NDRG2 expression [19], our result shows that treatment of iron chelators did not affect NDRG2 expression in SAS and OECM-1 cells

Summary

Introduction

Oral squamous cell carcinoma (OSCC) accounts for 90% of all oral cancers, which are the most commonly diagnosed malignancies, estimated at over 300,000 new cases annually around the world [1,2]. The higher iron demand in cancer cells due to rapid DNA synthesis and growth than in normal cells has implied the antitumor potential of iron chelators [6]. Di-2-pyridylketone 4,4-dimethyl-3thiosemicarbazone (Dp44mT), desferrioxamine (DFO), and deferasirox, applied as medical treatment for iron overload disease, have been shown to possess antitumor activity for certain cancers [5,6,7,8,9]. Prior studies regarding Dp44mT, DFO, and deferasirox have demonstrated that the inhibitory effects on cancer cell proliferation and metastasis of these three drugs were mediated by several pathways, such as increasing levels of apoptosis markers including p21, p53, and activation of mitogen-activated protein kinases (MAPKs), and decreasing levels of cyclins and cyclin-dependent kinase 2 (CDK2) [8,10,11]

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