A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness.

Yuki Katsura,Toshiyoshi Fujiwara,Takayuki Ninomiya,Shunsuke Kagawa,Toshiaki Ohara,Akihiro Matsukawa,Takuya Kato,Toru Narusaka,Tomonari Kasai,Boyi Xing,Hajime Kashima,Kazuhiro Noma,Yuehua Chen,Hiroaki Sato,Satoshi Komoto,Yasuko Tomono,Masaharu Seno,Hiroshi Tazawa,Yasuhiro Shirakawa

doi:10.3390/cancers11020177

Abstract

Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy.

Highlights

Iron is an essential element and plays crucial roles in our body, including roles in cell growth, proliferation, DNA synthesis, and energy metabolism
CDDP suppressed the proliferation of HSC-2 cells and OE33 cells in a dose-dependent manner (Figure 3C), but expression of some stemness markers remained unchanged or increased (Figure 3D). These results indicated that DFX effectively suppressed both proliferation and stemness in 11, cancer cell lines with high stemness status
Our results showed that DFX suppressed the stemness in cancer cells with high stemness status and that combination therapy with chemotherapy may be a novel approach against cancer stem cells (CSCs)

Summary

Introduction

Iron is an essential element and plays crucial roles in our body, including roles in cell growth, proliferation, DNA synthesis, and energy metabolism. Excess iron is associated with tumorigenesis in many types of human cancers [1,2,3] and is associated with cancer progression. These indicate that iron is an essential element for cancer cells and thought to be a therapeutic target. Our has shown antitumor explored asdepletion possible therapeutic interventions in various effect of iron therapy using an iron-deficient diettypes [7]. Our group has shown the antitumor effect of iron depletion therapy using an iron-deficient diet [7]

Methods

Results

Conclusion