ABSTRACT
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: IC50=160µM; 22GSCs: IC50=44µM) compared to MGMT non-expressing (33GSCs: IC50=1.5µM; 114GSCs: IC50=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.
Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , DNA Modification Methylases/metabolism , DNA Repair Enzymes/metabolism , Dacarbazine/analogs & derivatives , Electromagnetic Fields , Glioblastoma/metabolism , Tumor Suppressor Proteins/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/radiation effects , Cell Survival/drug effects , Cell Survival/radiation effects , Cells, Cultured , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , Dacarbazine/pharmacology , Glioblastoma/genetics , Humans , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/radiation effects , Neurons/drug effects , Neurons/radiation effects , Temozolomide , Tumor Suppressor Proteins/geneticsABSTRACT
The human nervous system maintains dominion over everything experienced in life, consolidating a constant barrage of stimuli and chemical fluctuation into memory, sense, emotion, and even character. Despite decades of productive investigation, comprehension of the nervous system's function and structure remain shrouded in mystery. Historically, the burden of elucidating these mysteries has fallen to neuroscientists bold enough to seek answers to this most nebulous vista. The legacy of one such neuroscientist, Jerzy Edwin Rose, endures today as a pillar of neuroscientific discovery. In the nascence of his career, Rose explored volumetric comparisons of human brain structure to that of other mammals, leading to the development of novel methods in neurophysiologic measurement and explanation. Rose would later segue mid-career into studies on the cooperation between the auditory cortex and thalamus, resulting in increased understanding of its functioning, structure, and anatomy. During the final saga of his long, fruitful career, Rose explored the electrophysiology of the auditory system, leading to novel methods using modern technology. Ultimately, the vast breadth of Rose's contributions to neuroscience has diminished the field's mystery, setting forth momentous groundwork for future discovery, and the inspiration to carry on in the spirit of his bold curiosity.
