Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization.

Keiichiro Hayashi,Kohji Takei,Naohisa Ogo,Kazuhito Tomizawa,Fan-Yan Wei,Hiroki Nakayama,Tei-Ichi Nishiki,Katsuyoshi Takata,Hiroyuki Miyachi,Atsushi Fujimura,Hiroshi Yamada,Hiroshi Tazawa,Hiroyuki Michiue,Hideki Matsui,Akira Asai

doi:10.1038/srep23372

Abstract

Glioblastoma multiforme (GBM) is the most common malignant brain tumor with a median survival time about one year. Invasion of GBM cells into normal brain is the major cause of poor prognosis and requires dynamic reorganization of the actin cytoskeleton, which includes lamellipodial protrusions, focal adhesions, and stress fibers at the leading edge of GBM. Therefore, we hypothesized that inhibitors of actin polymerization can suppress GBM migration and invasion. First, we adopted a drug repositioning system for screening with a pyrene-actin-based actin polymerization assay and identified fluvoxamine, a clinically used antidepressant. Fluvoxamine, selective serotonin reuptake inhibitor, was a potent inhibitor of actin polymerization and confirmed as drug penetration through the blood–brain barrier (BBB) and accumulation of whole brain including brain tumor with no drug toxicity. Fluvoxamine inhibited serum-induced ruffle formation, cell migration, and invasion of human GBM and glioma stem cells in vitro by suppressing both FAK and Akt/mammalian target of rapamycin signaling. Daily treatment of athymic mice bearing human glioma-initiating cells with fluvoxamine blocked tumor cell invasion and prolonged the survival with almost same dose of anti-depressant effect. In conclusion, fluvoxamine is a promising anti-invasive treatment against GBM with reliable approach.

Highlights

Manufacturer Sigma-Aldrich Wako Pure Chemical Wako Pure Chemical Wako Pure Chemical Sawai Pharmaceutical Sigma-Aldrich Nacalai Tesque Sigma-Aldrich Mitsubishi Tanabe Pharma Daiichi Sankyo Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich neurons, astrocytes, and oligodendrocytes[4,5]
When the use of a new cancer drug is expanded to malignant brain tumors, especially Glioblastoma multiforme (GBM), their distribution, pharmacokinetics, and BBB permeability become an issue
We report identification of the antidepressant fluvoxamine as a potent inhibitor of actin polymerization, which is essential for cancer cell migration and invasion

Summary

Introduction

Manufacturer Sigma-Aldrich Wako Pure Chemical Wako Pure Chemical Wako Pure Chemical Sawai Pharmaceutical Sigma-Aldrich Nacalai Tesque Sigma-Aldrich Mitsubishi Tanabe Pharma Daiichi Sankyo Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich neurons, astrocytes, and oligodendrocytes[4,5]. Fluvoxamine inhibits GBM cell migration and invasion in vitro. To examine the in vitro effects of fluvoxamine on GBM cell migration and invasion, we performed a wound-healing and Matrigel invasion assay.

Results

Conclusion