Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts.

Masashi Okada,Asuka Sugai,Keita Togashi,Chifumi Kitanaka,Shuhei Suzuki,Masahiro Yamamoto

doi:10.3390/ijms222111633

Masashi Okada, Asuka Sugai + Show 4 more

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https://doi.org/10.3390/ijms222111633

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Abstract

Glioblastoma (GBM) is one of the deadliest of all human cancers. Developing therapies targeting GBM cancer stem cells or glioma stem cells (GSCs), which are deemed responsible for the malignancy of GBM due to their therapy resistance and tumor-initiating capacity, is considered key to improving the dismal prognosis of GBM patients. In this study, we found that folate antagonists, such as methotrexate (MTX) and pemetrexed, are selectively cytotoxic to GSCs, but not to their differentiated counterparts, normal fibroblasts, or neural stem cells in vitro, and that the high sensitivity of GCSs to anti-folates may be due to the increased expression of RFC-1/SLC19A1, the reduced folate carrier that transports MTX into cells, in GSCs. Of note, in an in vivo serial transplantation model, MTX alone failed to exhibit anti-GSC effects but promoted the anti-GSC effects of CEP1347, an inducer of GSC differentiation. This suggests that folate metabolism, which plays an essential role specifically in GSCs, is a promising target of anti-GSC therapy, and that the combination of cytotoxic and differentiation therapies may be a novel and promising approach to effectively eliminate cancer stem cells.

Highlights

Cancer stem cells (CSCs), considered the source of cancer tissue, comprise only a small population of tumor cells, but they remain and cause recurrence after treatment is considered successful at a glance because they are both resistant to therapy and have tumor-initiating ability
Focusing mainly on glioma stem cells (GSCs), which are CSCs of glioblastoma, we elucidated the mechanism of the maintenance of the stem cell properties of GSCs and developed treatment methods leading to loss of these properties through the induction of differentiation by targeting this mechanism [1,2,3,4,5]
DiIsncuthssisiosntudy, we discovered through in vitro experiments that human glioblastomaderivIendthGisSCstsuadrye, whieghdliyscsoevnesrietidvethtroouthgehfionlavtietraonetaxgpoenriimstesnMtsTtXhaatnhduPmEaMn,galinodbltahsatot mcealldearitvheids sGtrSoCnsgalyreinhdiguhcelydsbeyntshiteisveedtorutghse. fOonlatheeaontthaegrohnaisntds,MisToXgeannicddPifEfMere, natniadtethdaGt SceClsl and normal cells, fibroblasts and astrocytes, survived in the presence of folate antagonists

Summary

Introduction

Cancer stem cells (CSCs), considered the source of cancer tissue, comprise only a small population of tumor cells, but they remain and cause recurrence after treatment is considered successful at a glance because they are both resistant to therapy and have tumor-initiating ability. With a goal of reducing residual GSCs after differentiation therapies, we searched for GSC-killing drugs using a similar approach and identified a number of drugs that selectively inhibit the survival of GSCs, among which were inhibitors of oxidative phosphorylation, which is more strongly activated in GSCs than in nonGSCs [7,8]. Of note, among these GSC-selective cytotoxic drugs were folate antagonists. We aimed to clarify the mechanism of the selective cytotoxic effects of folate antagonists in vitro and evaluate their GSC-inhibitory effects in vivo

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