The effects of tumor treating fields and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells

Nov 21, 2016Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia

Effects of tumor treating fields and temozolomide on glioblastoma cells with and without MGMT protein

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Abstract

A ⩾10-fold increase in temozolomide resistance was observed in MGMT-expressing glioblastoma stem-like cells compared to non-expressing cells.

MGMT-expressing glioblastoma stem-like cells demonstrated significantly higher resistance to temozolomide compared to non-expressing cells.
Tumor treating fields (TTFields) inhibited the proliferation of MGMT-expressing cells at all tested doses, with optimal effectiveness at 200kHz.
At 200kHz, TTFields reduced both cell proliferation and tumor sphere formation in all tested glioblastoma stem-like cell lines.
The combination of TTFields at 200kHz and temozolomide exhibited an additive anti-cancer effect without affecting temozolomide resistance.

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A recent Phase 3 study of newly diagnosed glioblastoma (GBM) demonstrated the addition of tumor treating fields (TTFields) to temozolomide (TMZ) after combined radiation/TMZ significantly increased survival and progression free survival. Preliminary data suggested benefit with both methylated and unmethylated O-6-methylguanine-DNA methyl-transferase (MGMT) promoter status. To date, however, there have been no studies to address the potential interactions of TTFields and TMZ. Thus, the effects of TTFields and TMZ were studied in vitro using patient-derived GBM stem-like cells (GSCs) including MGMT expressing (TMZ resistant: 12.1 and 22GSC) and non-MGMT expressing (TMZ sensitive: 33 and 114GSC) lines. Dose-response curves were constructed using cell proliferation and sphere-forming assays. Results demonstrated a ⩾10-fold increase in TMZ resistance of MGMT-expressing (12.1GSCs: IC=160μM; 22GSCs: IC=44μM) compared to MGMT non-expressing (33GSCs: IC=1.5μM; 114GSCs: IC=5.2μM) lines. TTFields inhibited 12.1 GSC proliferation at all tested doses (50-500kHz) with an optimal frequency of 200kHz. At 200kHz, TTFields inhibited proliferation and tumor sphere formation of both MGMT GSC subtypes at comparable levels (12.1GSC: 74±2.9% and 38±3.2%, respectively; 22GSC: 61±11% and 38±2.6%, respectively; 33GSC: 56±9.5% and 60±7.1%, respectively; 114 GSC: 79±3.5% and 41±4.3%, respectively). In combination, TTFields (200kHz) and TMZ showed an additive anti-neoplastic effect with equal efficacy for TTFields in both cell types (i.e., ± MGMT expression) with no effect on TMZ resistance. This is the first demonstration of the effects of TTFields on cancer stem cells. The expansion of such studies may have clinical implications. 50 50 50 50

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The effects of tumor treating fields and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells

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