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Induction of brain tumor stem cell apoptosis by FTY720: a potential therapeutic agent for glioblastoma
Adriana Estrada-Bernal1, Kamalakannan Palanichamy, Abhik Ray Chaudhury
1Department of Pathology, The Ohio State University, Columbus, Ohio, USA.
Abstract:
FTY720 is a sphingosine analogue that down regulates expression of sphingosine-1-phosphate receptors and causes apoptosis of multiple tumor cell types, including glioma cells. This study examined the effect of FTY720 on brain tumor stem cells (BTSCs) derived from human glioblastoma (GBM) tissue. FTY720 treatment of BTSCs led to rapid inactivation of ERK MAP kinase, leading to upregulation of the BH3-only protein Bim and apoptosis. In combination with temozolomide (TMZ), the current standard chemotherapeutic agent for GBM, FTY720 synergistically induced BTSC apoptosis. FTY720 also slowed growth of intracranial xenograft tumors in nude mice and augmented the therapeutic effect of TMZ, leading to enhanced survival. Furthermore, the combination of FTY720 and TMZ decreased the invasiveness of BTSCs in mouse brains. FTY720 is known to cross the blood-brain barrier and recently received Food and Drug Administration approval for treatment of relapsing multiple sclerosis. Thus, FTY720 is an excellent potential therapeutic agent for treatment of GBM.
Insights
FTY720 effectively targets brain tumor stem cells (BTSCs) by inducing apoptosis and enhancing chemotherapy. This drug shows promise in slowing glioblastoma growth and reducing invasiveness in preclinical models.
Area of Science:
- Oncology
- Neuro-oncology
- Pharmacology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options.
- Brain tumor stem cells (BTSCs) are implicated in GBM recurrence and therapeutic resistance.
- FTY720, a sphingosine analogue, modulates sphingosine-1-phosphate receptors and induces apoptosis in tumor cells.
Purpose of the Study:
- To investigate the efficacy of FTY720 against human glioblastoma stem cells (BTSCs).
- To evaluate the synergistic effect of FTY720 in combination with temozolomide (TMZ) for GBM treatment.
- To assess the impact of FTY720 on tumor growth, survival, and invasiveness in preclinical models.
Main Methods:
- Treatment of BTSCs with FTY720 and/or TMZ.
- Analysis of ERK MAP kinase signaling pathway and Bim protein expression.
- Assessment of BTSC apoptosis and proliferation.
- Evaluation of FTY720 and TMZ efficacy in intracranial xenograft mouse models.
Main Results:
- FTY720 induced BTSC apoptosis via ERK inactivation and Bim upregulation.
- Combination therapy with FTY720 and TMZ demonstrated synergistic BTSC apoptosis.
- FTY720 slowed tumor growth, enhanced TMZ efficacy, and improved survival in mice.
- The FTY720-TMZ combination reduced BTSC invasiveness in the mouse brain.
Conclusions:
- FTY720 is a potent agent against GBM stem cells, acting through specific molecular pathways.
- Combined FTY720 and TMZ therapy offers a synergistic approach to GBM treatment.
- FTY720's ability to cross the blood-brain barrier and its existing FDA approval make it a promising candidate for GBM therapy.
