The Multi-Faceted Effect of Curcumin in Glioblastoma from Rescuing Cell Clearance to Autophagy-Independent Effects.

Larisa Ryskalin,Alessandro Frati,Gloria Lazzeri,Carla L Busceti,Francesca Biagioni,Francesco Fornai

doi:10.3390/molecules25204839

Abstract

The present review focuses on the multi-faceted effects of curcumin on the neurobiology glioblastoma multiforme (GBM), with a special emphasis on autophagy (ATG)-dependent molecular pathways activated by such a natural polyphenol. This is consistent with the effects of curcumin in a variety of experimental models of neurodegeneration, where the molecular events partially overlap with GBM. In fact, curcumin broadly affects various signaling pathways, which are similarly affected in cell degeneration and cell differentiation. The antitumoral effects of curcumin include growth inhibition, cell cycle arrest, anti-migration and anti-invasion, as well as chemo- and radio-sensitizing activity. Remarkably, most of these effects rely on mammalian target of rapamycin (mTOR)-dependent ATG induction. In addition, curcumin targets undifferentiated and highly tumorigenic GBM cancer stem cells (GSCs). When rescuing ATG with curcumin, the tumorigenic feature of GSCs is suppressed, thus counteracting GBM establishment and growth. It is noteworthy that targeting GSCs may also help overcome therapeutic resistance and reduce tumor relapse, which may lead to a significant improvement of GBM prognosis. The present review focuses on the multi-faceted effects of curcumin on GBM neurobiology, which represents an extension to its neuroprotective efficacy.

Highlights

Curcumin is a natural polyphenol extracted from the rhizome of Curcuma longa; it is known as turmeric [1] and was introduced to Europe in the 14th century as a culinary spice [2]
These data confirm that the effects of curcumin on GBM cancer stem cells (GSCs) are tightly bound to ATG induction, and they further strengthen the notion that the ATG-dependent differentiation, migration arrest, and occluded invasion induce by curcumin may be promising in the adjunct therapeutic of glioblastoma multiforme (GBM)
Extensive research in the past two decades demonstrates the beneficial effects of phytochemicals in general, and especially curcumin, in a wide range of human diseases, encompassing neurogenerative disorders (NDDs) and brain tumors, and GBM

Summary

Introduction

Curcumin is a natural polyphenol extracted from the rhizome of Curcuma longa; it is known as turmeric [1] and was introduced to Europe in the 14th century as a culinary spice [2]. While finely tuned mTOR signaling is essential for normal CNS development, GSCs take advantage of an improper mTOR activity to fuel tumor growth and infiltration [69] These cells feature a robust up-regulation of mTOR, and a marked ATG suppression, which relates to key biological properties, such as increased self-renewal, marked proliferation, and invasion. In experimental settings, rescuing ATG associates with an inhibition of cell proliferation and invasion [52,69,72,74,77,78,79] In this regard, various studies have shown that curcumin exerts anti-cancer activity by inhibiting mTOR signaling, which among various effects activates the ATG pathway [53,54,64,80,81,82].

Curcumin Suppresses GSCs’ Tumorigenicity through ATG Induction

Effects of Curcumin on GBM beyond ATG Induction

Curcumin Induces Pro-Apoptotic Pathways in GBM Cells

Concluding Remarks

Methods