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Table of Contents
REVIEW
Year : 2022  |  Volume : 5  |  Issue : 3  |  Page : 81-86

Research progress of drug resistance mechanisms to temozolomide in glioblastoma: A narrative review


Department of Neurosurgery, SengKang Community Hospital, Singapore

Date of Submission06-Sep-2022
Date of Decision16-Sep-2022
Date of Acceptance22-Sep-2022
Date of Web Publication13-Oct-2022

Correspondence Address:
Dr. Allen Lu
Anchorvale Street, SengKang Community Hospital
Singapore
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_24_22

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  Abstract 


Glioblastoma multiforme (GBM) is the most common malignant tumor in the adult central nervous system, and surgery combined with radiotherapy and chemotherapy represents the main treatment regimens. Temozolomide (TMZ) is currently the first-line chemotherapeutic agent used in GBM therapy and is widely used subsequent with surgical resection of GBM. TMZ can significantly prolong the survival time of patients with glioma. However, the high incidence of resistance to TMZ, which seriously affects the overall outcome of GBM treatment, is a serious concern facing clinicians. The mechanisms of resistance to TMZ in patients with GBM include biological processes involving DNA damage repair, cellular autophagy, glioma stem cells, and the tumor microenvironment. Therefore, exploring the mechanisms inducing GBM resistance to TMZ treatment and how to effectively reduce TMZ resistance and improve its efficacy has become an urgent question. This review summarizes the effects and mechanisms of TMZ resistance in the treatment of glioma. It is hoped that intensive investigation of the mechanisms of resistance of TMZ to GBM can lay the foundation for successful outcomes in patients with GBM.

Keywords: DNA damage, glioblastoma, glioma stem cells, resistance mechanisms, temozolomide


How to cite this article:
Lu A. Research progress of drug resistance mechanisms to temozolomide in glioblastoma: A narrative review. Glioma 2022;5:81-6

How to cite this URL:
Lu A. Research progress of drug resistance mechanisms to temozolomide in glioblastoma: A narrative review. Glioma [serial online] 2022 [cited 2022 Dec 1];5:81-6. Available from: http://www.jglioma.com/text.asp?2022/5/3/81/358553




  Introduction Top


Glioma is the most common primary intracranial malignant tumor in the adult central nervous system and mainly includes astroglioma, oligodendroglioma, ependymoma, and mixed glioma, and the highest grade glioblastoma multiforme (GBM) is the most common adult intracranial malignancy.[1] Currently, the standard approach to therapy in newly diagnosed GMB includes surgical resection followed by concurrent radiotherapy with temozolomide (TMZ) followed by further adjuvant TMZ.[2] Patients with high-grade glioma have a poor prognosis, and the median survival time of patients with untreated glioblastoma is essentially <3 months.[3] GBM grows invasively and often invades surrounding normal tissues, the anatomical location of some gliomas is relatively indistinct; thus, it is often difficult to achieve radical resection, and the recurrence rate is high,[4] so comprehensive treatment of patients with gliomas is very important to improve prognosis. The results of phase III clinical trials have confirmed that the combination of TMZ with radiotherapy can significantly prolong the median survival by 14.6 months in patients with glioblastoma.[5]

TMZ is an oral alkylating agent, characterized by effective passage through the blood-brain barrier, and has an oral bioavailability of nearly 100%. TMZ can significantly improve the prognosis of patients with malignant glioma, compared to traditional chemotherapy drugs, despite its severe adverse effects, such as myelosuppression, and it is considered the best first-line drug in the treatment of glioma. However, since TMZ has been used clinically for glioma, the treatment outcomes show that median survival is still not significantly prolonged and the clinical response rate is <45%.[6] Some patients receiving TMZ show good immediate efficacy, but poor long-term outcomes. Pilar González-Gómez depicts that the proportion of patients with glioma relapsing after TMZ treatment and not responding to further TMZ treatment is as high as 90%.[7] The reason is that glioma cells have primary or secondary resistance to TMZ. Therefore, how to reduce TMZ drug resistance, improve chemosensitivity, and reduce the recurrence rate in patients are urgent problems that must be solved in the clinical treatment of GBM. The mechanism of resistance to TMZ in glioma cells is complex. In this article, the current research progress and related solutions to overcome TMZ-resistance mechanism in the treatment of patients with GBM are reviewed.


  Retrieval Strategy Top


Literature review was electronically performed using the PubMed database. The following combinations of key words were used to initially select the articles to be evaluated: drug resistance and glioma, drug resistance and glioblastoma, temozolomide and glioma, temozolomide and glioblastoma, drug resistance, and temozolomide. Most of the elected studies (80% of all references) were published from 2004 to 2020. An ancient publication from 1976 was included in consideration to its relevance in the mast cell field.


  Pharmacological Effects of Temozolomide Top


TMZ is a lipophilic drug and acts as a potent alkylating agent. As a precursor drug, TMZ is not metabolized by the liver. Its chemical name is 3,4-dihydro-3-methyl-4-oxoimidazole. 5-(3-Methyl-1-triazen-1-yl) imidazole-4-carboxamide is the active metabolite of TMZ. The resulting reactive methyl diazonium ion methylates DNA at the N7 position of guanine (N7-MeG; 70%), followed by methylation at the N3 position of adenine (N3-MeA; 9%), and the O6 position of guanine (O6-MeG; 6%). The latter of methylation at O6-MeG is considered the lethal step and mediates the cytotoxic activity of TMZ. Glioma cells have many defense mechanisms against the action of TMZ, due to their ability to eliminate methyl groups or alter the DNA mismatch repair system, making them resistant to treatment with TMZ.

Repair of DNA damage is associated with resistance to temozolomide drugs

TMZ after entering tumor cells can lead to DNA methylation, which in turn can interfere with cell DNA replication, cause DNA damage, and inhibit tumor cell proliferation. Under this condition, cells activate the DNA damage repair mechanisms, DNA crosslinking and breakage can cause cell death. Meanwhile, it can restore the normal gene sequence structure through various DNA repair mechanisms, which can induce apoptosis, to maintain the relative stability of genetic information.[8] However, GBM cells have an extremely strong DNA damage repair system and complex damage repair mechanisms, thus preventing the DNA of the GBM cells from being damaged by alkylating agents, which are important for mediating the resistance of GBM to TMZ.[9] Among GBM DNA damage repair mechanisms, recent studies have focused mainly on O6-methylguanine-DNA methyltransferase (MGMT), mismatch repair (MMR), and genes that regulate the function of DNA damage repair.[10]

MGMT-mediated glioblastoma multiforme drug resistance

MGMT expression varies greatly between tumors. In lung cancer, ovarian cancer, and in breast cancer and leukemia the expression of MGMT is high, but it is low in glioma, malignant melanoma, and pancreatic cancer. MGMT is a key enzyme in the repair of cytotoxic methyl adducts, which was first detected in brain tumors in 1991 at the biochemical, molecular, and genetic levels by Ostrowski et al.[11] Among all DNA repair mechanisms, MGMT repair is one of the simplest and highly efficient mechanisms and is also the most important regulatory molecule responsible for repairing DNA damage in glioma cells caused by alkylating agents.[12] The main effect of MGMT is to reverse TMZ activity in the DNA before TMZ induces DNA damage. MGMT can irreversibly transfer the guanine O6 alkyl group in damaged DNA to MGMT itself at the cysteine residue 145, the structure and function of the alkylated DNA to protect tumor cells from TMZ damage, leads to treatment failure, while MGMT itself accepts the alkyl group[13] in a suicidal process.[14] Subsequently, MGMT is degraded by the proteasome and no longer participates in cycling functions. No other proteins participate in the entire process, and MGMT has been used both as a methyltransferase and as a methyl receptor protein. Therefore, MGMT is able to resist TMZ-induced methylation damage, while the expression of MGMT in GBM cells is relatively stable and higher than that of other types of gliomas.[15] This protective mechanism of MGMT is seen in various cell lines and allogeneic human transplant models, which is also the main reason for the commonly observed resistance to alkylating agents induced by TMZ. TMZ can not only remove the methyl groups attached to guanine at position O6 but can also remove other alkyl groups such as ethyl, isopropyl, and butyl.[16] In comparison, MGMT removes methyl groups[16] much faster than other alkyl groups. The elucidation of the key molecules and signaling pathways that regulate MGMT has become a research hotspot in the study of TMZ drug resistance. A recent study shows that MGMT is the only protein that can remove the guanine O6 complex from DNA, so the clinical level of MGMT detection may reflect the sensitivity of TMZ in different individuals.[17] That is, detecting the level of MGMT and its content in malignant glioma cells provides a good marker for patients planning to receive TMZ and provides a basis for assessing drug sensitivity and patient survival.

Interferons are a special class of cytokines, produced by a variety of cells, with certain antitumor activity and resistance to viral infection and immunomodulatory effects. In one study, in combination with interferon-β, the effects of TMZ were significantly enhanced by,[18] and tumor volume was significantly reduced. This is because interferon-β can not only directly exert a cytotoxic effect but it can also enhance the sensitivity of the glioma cell to TMZ by downregulating the expression of MGMT. Therefore, MGMT inhibitors are observed to significantly improve the efficacy of TMZ, providing a broad prospect for future clinical applications.

Resistance to mismatch repair-mediated temozolomide drugs

The MMR system was first identified in  Escherichia More Details coli, and the family includes multiple protein members (MSH2, MSH6, MLH1, and PMS2).[19] In gliomas, the DNA repair mechanism occurs after DNA damage. The MMR can antagonize the damaging effects of TMZ treatment on GBM cells and repair the damaged DNA, resulting in a reduced sensitivity of GBM to TMZ. Some studies have suggested that the “ineffective repair” mode is the main mechanism of MMR-induced apoptosis. Defects in the MMR system can cause mismatches in the cell that cannot be detected or repaired, thus avoiding DNA breakage, and also represents an important cause of resistance to TMZ in tumor cells.

Defects in the MMR gene can lead to loss of MMR function after DNA replication, while loss of MMR function leads to failure to repair TMZ-induced mismatch repair. If O6-methylguanine and thymine persist, these will lead to further base-pair mismatches that cannot be identified and repaired, the tumor avoids DNA breakage and eventually leads to gene mutation, accelerating the malignant potential of GBM, causing GBM cell resistance[20] to TMZ. In patients with recurrent GBM, mutations in MMR-related enzyme class genes lead to tumor resistance to TMZ, and glioma growth increases more rapidly.[21] The impaired MMR pathway is caused by mutations in the MMR protein complex, resulting in the inability of MMR to recognize TMZ O6-methylguanine DNA adducts induced by MMR. These mutations cause the DNA mismatch to continue during replication and allow the cell cycle to proceed, allowing the effects of TMZ treatment to be reduced.[22] Furthermore, these mutations may be present in the cell cycle or may be acquired[23] during TMZ treatment. Given its importance, we should develop strategies able to restore the MMR system to improve the efficacy of TMZ. Thus, both unsuccessful MMR and defective MMR render the GBM resistant to TMZ treatment.

The base excision repair-mediated temozolomide resistance

In addition to causing methylation at guanine O6, TMZ can also methylate guanine n7 and adenine n3, which represents 80% of all methylation and is potentially cytotoxic. This methylation at positions n7 and n3 can be repaired with base excision repair (BER) systems. BER is primarily responsible for repairing DNA damage caused by reactive oxygen species, ionizing radiation, and alkylating agents.[24] If the associated enzyme is deactivated by BER, it can cause lethal cell damage. Some tumors with an intact BER function, therefore, can repair TMZ-mediated damage to n3 methylation, thus exhibiting resistance to TMZ. Compared to MMR, BER is the main DNA repair pathway for the repair of DNA base damage.

Studies have confirmed that targeted inhibition of the main members of the BER pathway reverses resistance to TMZ in glioma.[25] Existing BER inhibitors act primarily on glycosylase-mediated base resection, while overexpression of MPG enhances the initiation response and when combined with inhibitors of BER can significantly increase the chemotherapy effect[26] of tumor cells by TMZ in the GBM cell lines ln428 and t98g.

There is evidence that the BER mechanism plays an important role in the resistance process of GBM-TMZ.[27] The DNA damage repair mechanisms such as MMR and BER are involved in intrinsic or acquired resistance to glioma treatment with TMZ and targeting the modulation of DNA repair enzymes is an effective strategy for increasing the chemosensitivity to TMZ. Although its effectiveness is currently validated at cellular and animal levels, the toxic side effects on normal cells may limit evaluation in clinical trials. Moreover, it is difficult to effectively reverse drug resistance in glioma because the molecular signaling pathways involved in tumor drug resistance are very complex and different signaling pathways crosstalk and compensate for each other.[27] Targeted drugs act on a single target but do not provide comprehensive treatment. Therefore, it is very difficult to treat glioma clinically, and more in-depth research is urgently needed to provide more effective strategies.

Genes that regulate DNA repair

TMZ-induced DNA methylation does not directly trigger GBM cell death; it requires accumulating DNA damage through DNA replication and MMR following methylation, leading to the formation of DNA double-strand breaks during which X-ray repair cross-complementing gene 3 (XRCC3) plays a key regulatory role. In physiological situations, XRCC3 is essential for maintaining genome integrity and cell survival, while XRCC3 expression increases in high-grade gliomas, and overexpressed XRCC3 can promote double strand break repair through homologous recombination, and can then protect GBM cells from TMZ-induced cell death, apoptosis, and cell cycle inhibition, mechanisms that are directly involved in the formation of TMZ resistance. By eliminating the expression of XRCC3, the effects of double strand break repair induced by TMZ are significantly reduced and the sensitivity of GBM to TMZ increases greatly.[28] Additionally, the X-linked alpha thalassemia mental retardation syndrome (ATRX) gene can participate in resistance of GBM to TMZ treatment by regulating DNA damage repair. Silencing of the ATRX gene can inhibit DNA replication and damage repair, which can then inhibit GBM growth and invasion and increase sensitivity to TMZ treatment.[29] Therefore, the expression of the ATRX gene is also a marker of a better prognosis and prolonged survival in patients with glioma.

Glioma stem cells and temozolomide drug resistance

Glioma stem cells (GSCS) represent a rare subset of cells with “stem cell characteristics” in glioma tissue, and have the characteristics of self-renewal, infinite proliferation, and multipotential differentiation. GSCS often express characteristic marker molecules on the cell surface, such as CD133, CD15, SSEA1, and Nestin. In 1992, Reynolds et al.[30] first proposed that the presence of GSCS in gliomas of mammals, including humans, a finding that was subsequently confirmed by numerous studies. The proportion of GSCS ranges from 0.3% to 9.1% of due to the different pathological types and grades of glioma. A study by Kondo et al.[31] reported that the GSCS represented approximately 0.4% in the c6 glioma cell lines. The above studies show that the proportion of GSCS is closely related to the pathological type and malignancy of the tumors, although there are large differences in the proportion of GSCS among the various tumor types. Currently, GSCS-like cells are believed to be one of the originating cells of GBM. GSCS have stronger drug resistance compared to ordinary glioma cells,[32] which is an important reason why GBM is extremely prone to relapse, and is also the main source of tolerance of GBM to chemoradiotherapy, playing an important role in the occurrence, development, and recurrence of GBM. With regard to the relationship between GSCS and resistance to GBM, it is widely believed that the presence of GSCS causes resistance of GBM cells to drugs such as TMZ, leading to a poor therapeutic effect, but the mechanism needs to be further elucidated. Auffinger et al.[33] believed that after treatment with chemotherapeutic drugs such as TMZ, some tumor cells in the glioma will become GSCS, and this type of cells will show stronger resistance to chemotherapeutic drugs, ultimately affecting the therapeutic effect.

Another significant feature of GSCS is the high expression of transporter proteins associated with drug excretion on the cell surface, which easily leads to a multidrug resistance phenomenon. The high expression in ABCG2 GSCS is the main cause of GSCS resistance to TMZ.[34] Existing tumor treatments target most cells within tumor tissue rather than tumor stem cells. The presence of GSCS better explains the biological behavior of glioma resistance at the cellular level. A small group of side population cells are also present in gliomas, and when gliomas undergo TMZ treatment, the number of cells increases, the expression of ABCG2 increases, and the resistance of cells increases. According to Bleau et al.,[35] side population cells are a cell model of GSCS and play an important role in chemoresistance. In addition, ABCG2 may be the root cause of drug resistance to GSCS and may serve as a new marker of GSCS. Future studies on glioma treatment should focus on how to remove tumor stem cells or improve the sensitivity of drugs to tumor stem cells; overcoming the drug resistance problem of tumor stem cells may be the key to our successful glioma treatment.

Other mechanisms of resistance to temozolomide

Hypoxia

In the hypoxic microenvironment, gliomas can strongly resist apoptosis, which contributes to tumor adaptation to the cytotoxic effects of chemotherapeutic agents. Hypoxia-induced high expression of miR-26a within GBM mediates the BAX/BCL-2-related cell death factor pathway to inhibit mitochondrial apoptotic activity and reduce the cytotoxic effect of TMZ.[36] Hypoxia induces the calcium opening of potassium ion channels activated on the surface of the GBM, increasing the invasive capacity and chemo-resistance of GBM. With the stress state caused by hypoxia, tumor cells often appear in anaerobic glycolysis, resulting in a reduced pH within and around cells, improving p-glycoprotein channel pump activity, and reducing GBM sensitivity to chemotherapy.

Related signaling pathways

In addition to mechanisms such as DNA damage repair, the activation of the cell survival signaling pathway is an important mechanism of resistance to TMZ, allowing tumor cells to survive by inhibiting apoptotic signaling even when DNA damage is not repaired. Signaling pathways such as PI3K/AKT and JAK2/STAT3 are important signaling pathways responsible for developing drug resistance to TMZ in glioma. It has been shown that the PI3K/AKT signaling pathway in glioma is abnormally activated, and can further activate multiple downstream signaling pathways, promoting the proliferation of tumor cells, and inhibiting their apoptosis. Inactivation of the AKT mutation has been shown to restore tumor cell sensitivity to TMZ, and therefore the AKT pathway is a valid pathway to improve the efficacy of TMZ. The miR-223 regulates pax6 expression and then activates the PI3K/AKT pathway to improve the proliferation capacity of glioblastoma stem cells and resistance of[37] to TMZ. The appearance of resistance to glioma drugs has been shown to be associated with the activation of the Wnt/β-catenin pathway, which in turn can affect the expression of the MGMT gene and thus cause resistance in glioma cells.[38]


  Limitations Top


The resistance mechanism of TMZ is complex, although this review has provided an overview of the many regulatory processes of resistance mechanisms towards TMZ during GBM treatment, but no single mechanism can independently explain or overcome the resistance hurdle. There are further problems to be addressed, which require a more intensive study of relevant resistance mechanisms. The recent development of multiple studies combining single-cell omics, high-throughput proteomics, and metabolomics will provide extremely beneficial assistance in the systematic elucidation of the mechanism of resistance to TMZ.


  Conclusions Top


GBM is the most malignant and aggressive brain glioma, it easily relapses, and the long-term survival rate is very low. Currently, it can only be eradicated by surgery, supplemented by chemoradiation. As an oral antitumor drug, TMZ can effectively cross the blood − brain barrier. Its myelosuppression, nausea, vomiting, and other adverse reactions, limit its clinical application and treatment effect, although TMZ has broad prospects for clinical application. However, GBM is prone to developing drug resistance to the first-line chemotherapy drug TMZ. In addition to some tumor cells that are naturally insensitive to TMZ, some originally sensitive tumor cells will also gradually develop acquired drug resistance in the chemotherapy process, greatly influence the outcome of postoperative chemotherapy and limit its efficacy. This review shows that DNA damage repair, cell autophagy, and tumor stem cells play important roles during the formation of acquired drug resistance to TMZ.

The question of how to overcome tumor drug resistance and improve the efficacy of chemotherapy drugs such as TMZ is an urgent problem that must be solved clinically. Currently, improved treatment options for its resistance mechanisms, such as low-dose long-term medication, intensive regimen, MGMT depletion, or competitive inhibitors combined with MGMT, can increase tumor cell sensitivity to TMZ. In future, identifying the resistance mechanism will allow a more effective treatment target and combination treatment for different tumor patients. The targeting of resistance factors active against malignant glioma chemotherapy will allow a predictable, targeted new era of individualized treatment, able to improve the curative effects of chemotherapy, and finally achieving the objective of improving the patient prognosis.

Acknowledgments

Nil.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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