Potential Strategies Overcoming the Temozolomide Resistance for Glioblastoma

Abstract

Glioblastoma (GBM) is a highly malignant type of primary brain tumor with a high mortality rate. Although the current standard therapy consists of surgery followed by radiation and temozolomide (TMZ), chemotherapy can extend patient's post-operative survival but most cases eventually demonstrate resistance to TMZ. O⁶-methylguanine-DNA methyltransferase (MGMT) repairs the main cytotoxic lesion, as O⁶-methylguanine, generated by TMZ, can be the main mechanism of the drug resistance. In addition, mismatch repair and BER also contribute to TMZ resistance. TMZ treatment can induce self-protective autophagy, a mechanism by which tumor cells resist TMZ treatment. Emerging evidence also demonstrated that a small population of cells expressing stem cell markers, also identified as GBM stem cells (GSCs), contributes to drug resistance and tumor recurrence owing to their ability for self-renewal and invasion into neighboring tissue. Some molecules maintain stem cell properties. Other molecules or signaling pathways regulate stemness and influence MGMT activity, making these GCSs attractive therapeutic targets. Treatments targeting these molecules and pathways result in suppression of GSCs stemness and, in highly resistant cases, a decrease in MGMT activity. Recently, some novel therapeutic strategies, targeted molecules, immunotherapies, and microRNAs have provided new potential treatments for highly resistant GBM cases. In this review, we summarize the current knowledge of different resistance mechanisms, novel strategies for enhancing the effect of TMZ, and emerging therapeutic approaches to eliminate GSCs, all with the aim to produce a successful GBM treatment and discuss future directions for basic and clinical research to achieve this end.

Keywords: chemosensitivity; glioma; temozolomide.

Fig. 1

TMZ resistant mechanism. The causes of TMZ resistance are mainly DNA repair system, autophagy, and GSC. The MGMT and MMR systems remove the O⁶-guanine methylation, followed by usual DNA replication. Activated BER also contributes to DNA repair through removal of the methylation of N⁷-guanine and the N³-adenine. TMZ-induced autophagy via the ATM/AMPK pathway can induce AVO formation, LC3 aggregation, which are essential for autophagosome and lysosome interaction, facilitating cytoprotective autophagy and cell survival. GSCs may change their phenotype to TMZ resistant GSCs or differentiate into TMZ resistant GBM cells via tumor microenvironment modulation, chemoradiotherapy, or hypoxic condition. On the other hand, differentiated GBM cells can re-acquire stem cell capacity through reprogramming by the tumor microenvironment modulation. AMPK: AMP-activated protein kinase, ATM: ataxia telangiectasia mutated, AVO: acidic vesicular organelles, BER: base excision repair, GSC: glioblastoma stem cell, LC3: microtubule associated protein light chain 3, MGMT: methylguanine methyltransferase, MMR: mismatch repair, TMZ: Temozolomide, ULK: unc51-like kinase.

Fig. 2

Potential therapeutic approach enhancing the effect of TMZ. TMZ resistance by DNA repair is divided into MGMT independent and dependent mechanisms. Therapeutic approaches to overcome the former include methylation of the MGMT promoter with O⁶-BG, IFNβ, and GSK3β inhibition and depletion of MGMT by ddTMZ. Currently, PARP inhibition is the only available intervention for the latter mechanism. Circled m represents a methyl group. APNG: alkylpurine-DNA-N-glycosylase, GSK3β: glycogen synthase kinase 3β, INFβ interferon-β, MPG: N-methylpurine DNA glycosylase, O⁶-BG: O⁶-benzylguanine, PARP: poly (ADP-ribose) polymerase.

Fig. 3

Treat the GSCs based on TMZ. JNK, MEK/ERK pathways, and Wnt signaling maintain extensive proliferation and self-renewal ability of GSCs in a MGMT dependent manner. Aurora-A kinase, SOX2, and BMP regulate GSC stemness and correlate with tumor aggressiveness and poor prognosis. Targeting these molecules is a promising therapeutic strategy to enhance TMZ. BMP: bone morphogenetic proteins, ERK: extracellular signal regulated kinase, JNK: c-Jun N-terminal kinase, MEK: mitogen-activated protein kinase, SOX2: sex determining region Y-box 2.