Comparative analysis of the effects of a sphingosine kinase inhibitor to temozolomide and radiation treatment on glioblastoma cell lines

• Verfasst von: Cisneros Castillo, Liliana del Rocío [VerfasserIn]
• Verfasst von: Klein, Carmen [VerfasserIn]
• Verfasst von: Abdollahi, Amir [VerfasserIn]
• Verfasst von: Weber, Klaus-Josef [VerfasserIn]
• Verfasst von: Dokić, Ivana [VerfasserIn]
• Titel: Comparative analysis of the effects of a sphingosine kinase inhibitor to temozolomide and radiation treatment on glioblastoma cell lines
• Verf.angabe: Liliana R. Oancea-Castillo, Carmen Klein, Amir Abdollahi, Klaus-Josef Weber, Anne Régnier-Vigouroux & Ivana Dokic
• E-Jahr: 2017
• Jahr: 14 Jun 2017
• Umfang: 7 S.
• Fussnoten: Accepted author version posted online: 11 May 2017, published online: 14 Jun 2017 ; Gesehen am 10.09.2018
• Titel Quelle: Enthalten in: Cancer biology & therapy
• Ort Quelle: Georgetown, Tex. : Landes Bioscience, 2002
• Jahr Quelle: 2017
• Band/Heft Quelle: 18(2017), 6, Seite 400-406
• ISSN Quelle: 1555-8576
• DOI: doi:10.1080/15384047.2017.1323583
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Glioblastoma
• Sach-SW: GPx1
• Sach-SW: oxidative stress
• Sach-SW: radiosensitivity
• Sach-SW: sphingosine kinase inhibition
• Sach-SW: temozolomide
• Sach-SW: X-rays
• K10plus-PPN: 1580825982

Abstract

Glioblastoma multiforme (GBM) exhibits high resistance to the standard treatment of temozolomide (TMZ) combined with radiotherapy, due to its remarkable cell heterogeneity. Accordingly, there is a need to target alternative molecules enhancing specific GBM autocrine or paracrine mechanisms and amplifying the effect of standard treatment. Sphingosine 1-phosphate (S1P) is such a lipid target molecule with an important role in cell invasion and proliferation. Sphingosine kinase inhibitors (SKI) prevent S1P formation and induce increased production of reactive oxygen species (ROS), which may potentiate radiation cytotoxicity. We analyzed the effect of SKI singular versus combined treatments with TMZ and radiation on 2 human GBM cell lines characterized by a lack of MGMT expression and low or high expression of the anti-oxidant enzyme, glutathione peroxidase 1 (GPx1). Effects were drug concentration-, cell line-dependent and partly ROS-mediated. Clonogenic survival assay demonstrates that SKI was more effective than TMZ in increasing the sensitivity of U87 cells, which express low GPx1 amount, to a 2 Gy X-ray dose. Addition of both SKI and TMZ drastically decreased U87 cells survival compared with the combination temozolomide/radiation. SKI less effectively than TMZ sensitized LN229 cells to the 2 Gy X-ray dose. Its combination to TMZ in absence of irradiation was as efficient as TMZ combination with X-ray. We provide first evidence for SKI as an alternative or complementary treatment to TMZ, and for efficient combinations of low doses of drugs and X-ray. These may help as novel bi-modal and tri-modal therapies to contend with GBM heterogeneity.