Temozolomide resistance in glioblastoma multiforme

Abstract

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.

Fig. 1

Mechanism of Temozolomide and Temozolomide resistance. Temozolomide (TMZ) modifies DNA or RNA at N⁷ and O⁶ sites on guanine and the N³ on adenine by the addition of methyl groups. The methylated sites can remain mutated, be fixed by DNA mismatch repair (MMR), be removed by base excision repair (BER) by the action of a DNA glycosylase such as, alkylpurine-DNA-N-glycosylase (APNG), or deakylated by the action of a demethylating enzyme such as O⁶-methylguanine methyltransferase (MGMT). Cells are TMZ sensitive when MMR is expressed and active. When MGMT, APNG, and BER proteins are expressed, GBM cells are resistant to TMZ.