Temozolomide (TMZ) is an oral alkylating agent used to treat glioblastoma multiforme (GBM) and astrocytomas. However, at least 50% of TMZ treated patients do not respond to TMZ. This is due primarily to the over-expression of O6-methylguanine methyltransferase (MGMT) and/or lack of a DNA repair pathway in GBM cells. Multiple GBM cell lines are known to contain TMZ resistant cells and several acquired TMZ resistant GBM cell lines have been developed for use in experiments designed to define the mechanism of TMZ resistance and the testing of potential therapeutics. However, the characteristics of intrinsic and adaptive TMZ resistant GBM cells have not been systemically compared. This article reviews the characteristics and mechanisms of TMZ resistance in natural and adapted TMZ resistant GBM cell lines. It also summarizes potential treatment options for TMZ resistant GBMs.
Keywords: AGT (also known as MGMT), O6-methylguanine-DNA alkyltransferase; AP-1, activator protein 1; APE1, apurinic/apyrimidine endonuclease/redox factor-1; APNG, Alkylpurine-DNA-N-glycosylase; Adaptive; BBB, blood-brain-barrier; BCRP1, breast cancer resistance protein 1; BER, base excision repair; BG, benzylguanine; C8orf4, Chromosome 8 open reading frame 4; EGFR, epidermal growth factor receptor; ERK1/2, Extracellular Signal Regulated Kinases 1 and 2; FDA, Food and Drug Administration; GBM, glioblastoma multiforme or glioblastoma; Glioblastoma; HDAC, histone deacetylase; IFN-β, Interferon-β; Intrinsic; JNK, Jun N-terminal kinase; KDM, Histone lysine demethylase; LC50, 50% cell death concentration; LIF, Leukemia inhibitory factor; MGMT, O6-methylguanine methyltransferase; MMR, DNA mismatch repair; MSH6, mutS homolog 6; MTIC, 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide; NAMPT, nicotinamide phosphoribosyl transferase; NF-κB, nuclear factor-Kappa B; NHA, normal human astrocytes; PARP, poly ADP ribose polymerase; Resistance; SAHA, N-hydroxy-N′-phenyl-octanediamide; STAT3, Signal Transducer and Activator of Transcription 3; TMZ, Temozolomide; TNFAIP3, Tumor necrosis factor-α-induced protein 3; Temodar; Temozolomide; VPA, Valproic acid; mTOR, mammalian target of rapamycin.