Open Access

Research progress of anti-glioma chemotherapeutic drugs (Review)

  • Authors:
    • Yi-Shu Zhou
    • Wei Wang
    • Na Chen
    • Li-Cui Wang
    • Jin-Bai Huang
  • View Affiliations

  • Published online on: March 30, 2022     https://doi.org/10.3892/or.2022.8312
  • Article Number: 101
  • Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Glioma is the most common primary intracranial malignancy in the central nervous system. At present, the most important treatment option is surgical resection of the tumor combined with radiotherapy and chemotherapy. The principle of operation is to remove the tumor to the maximal extent on the basis of preserving brain function. However, prominent invasive and infiltrative proliferation of glioma tumor cells into the surrounding normal tissues frequently reduces the efficacy of treatment. This in turn worsens the prognosis, because the tumor cannot be completely removed, which can readily relapse. Chemotherapeutic agents when applied individually have demonstrated limited efficacy for the treatment of glioma. However, multiple different chemotherapeutic agents can be used in combination with other treatment modalities to improve the efficacy while circumventing systemic toxicity and drug resistance. Therefore, it is pivotal to unravel the inhibitory mechanism mediated by the different chemotherapeutic drugs on glioma cells in preclinical studies. The aim of the present review is to provide a summary for understanding the effects of different chemotherapeutic drugs in glioma, in addition to providing a reference for the preclinical research into novel chemotherapeutic agents for future clinical application.

Introduction

Glioma is a malignancy that originates from glial cells. According to the World Health Organization (WHO) in 2016, gliomas can be classified into four grades, of which grade I and II are low-grade, whereas grade III and IV are high-grade (1). In 2021, WHO updated the molecular biomarkers of different tumor types, recommended the use of Arabic numerals for scoring, emphasized the importance of grading within tumor types, and brought more benefits and meaningful guidance for clinical practice (2). Glioblastoma (GBM) accounts for ~60% of all high-grade gliomas. High-grade gliomas can be observed in individuals of all ages, but are particularly common in men (35). Low-grade gliomas will typically relapse after initial treatment. Following recurrence, low-grade gliomas can transform into high-grade gliomas (68). The incidence of glioma accounts for ~40% of all malignancies in the central nervous system tumors, which is highly invasive and infiltrative (9). In addition, it has high recurrence rates and low 5-year survival rates, which poses a serious threat to human health (10). The median survival time of patients with glioma is only 15 months (11), whereas the 5-year survival rate is <10% (12). The etiology and mechanism underlying the pathogenesis of glioma remain unclear, but it has been demonstrated to show complex molecular characteristics, such as increases in chromosomes 7 and 19, loss of chromosomes 10 and 13, amplifications of EGFR and mouse double minute 2 homolog, mutations in PTEN, neurofibromatosis type 1, platelet-derived growth factor receptor α1, isocitrate dehydrogenase 1 and deletion of cyclin dependent kinase inhibitor 2A (13,14). Ionizing radiation exposure is also considered to be one of the causes of glioma (14,15).

At present, the standard treatment option for glioma is surgical resection combined with radiotherapy and chemotherapy (16). However, the long-term therapeutic efficacy is limited, where the main reasons are as follows: i) Due to the invasiveness of this malignancy, local resection of the tumor only removes the primary tumor but cannot remove the surrounding tissues where the tumor has already invaded (17); ii) the chemotherapeutic agent cannot reach the tumor due to the blood-brain barrier (BBB), which causes systemic toxicity and side effects, reducing the maximum efficacy (18,19); and iii) tumor cells develop internal resistance to the agent (20), thus exerting varying degrees of resistance to different types of chemotherapeutic drugs, minimizing the effect of chemotherapy. Therefore, major obstacles remain before glioma can be completely cured (20). The invasiveness of GBM is caused by the signal pathway of tyrosine kinase receptor (21). Tyrosine kinase inhibitors (TKIs) and signal pathways (PI3K/AKT, Wnt/β-catenin, Hedgehog and NF-κB) serve important roles in the progression of GBM (2224). TKIs selectively inhibit tumor growth and regulate cell proliferation, migration, apoptosis and angiogenic factors by activating intracellular signal transduction (25). Treatment strategies for glioma includes surgery, radiotherapy, chemotherapy, targeting and immunotherapy (25,26). However, chemotherapy agents when applied individually exert limited therapeutic effects (3). As such, different combinations of chemotherapeutic agents can be applied together to overcome drug resistance and reduce their toxic adverse effects (27). Drug delivery systems, such as nanoparticles, liposomes and polymer micelles can all transport chemotherapeutic drugs through the BBB to improve efficacy and enhance the targeting effects (27,28). Therefore, chemotherapy remains to be a basic component of multimodal therapeutic method for malignant glioma treatment (29). Postoperative application of chemotherapeutic drugs in patients with glioma serves an important role in preventing postoperative recurrence. Considering the existence of the BBB in the central nervous system, the ideal chemotherapeutic drug should be small in molecular weight, lipophilic, non-protein, and able to spread to the brain stroma through the BBB (30). The main obstacle to effective glioma chemotherapy is currently drug resistance development and the occurrence of toxic side effects. Therefore, there is demand for the development of novel agents and drug delivery systems to alleviate these two challenges for clinical application. A systematic literature search for eligible studies through the electronic search engine PubMed was performed. The keywords for searches were as follows: ‘Glioma’, ‘glioblastoma’ and ‘chemotherapeutic drugs’. Studies published in the past 10 years were searched using these keywords. The prevent review discusses the potential mechanism and application of various chemotherapeutic agents for glioma treatment.

Temozolomide

Preclinical study and combination therapy of temozolomide (TMZ)

TMZ is a first line chemotherapy drug for glioma (31) and a precursor alkylating agent (32). In addition, TMZ is a small molecule and lipophilic substance that can be taken orally and readily traverses through the BBB (33,34). Data from previous preclinical studies (16,27,3551) (Table I) showed that it can exert anticancer activity. Wang et al (35) treated C6 cells with TMZ (250-1,000 µM) for 24, 48 and 72 h. The results revealed that TMZ inhibited the proliferation, migration and invasion of C6 cells through the MEK/ERK signaling pathway, and downregulation of vascular endothelial growth factor (VEGF)-C expression to enhance the inhibitory effects of TMZ. The invasive growth and recurrence of gliomas are closely associated with tumor neovascularization. Tumor cells secrete a number of vascular growth factors such as VEGF to facilitate the growth of tumors (52). A previous study by Sonoda et al (53) have revealed that overexpression of VEGF can increase tumor volume and vascular permeability in mice. Effective inhibition of VEGF in gliomas has been previously shown to inhibit neovascularization. Bevacizumab (BEV) is an anti-angiogenic agent, such that treatment with the combination of BEV and TMZ did not weaken the effects exerted by TMZ. Grossman et al (54) revealed that TMZ combined with BEV treatment was able to inhibit VEGF to prolong the survival time of rats injected with U87 cells (109 days). Although TMZ can exert inhibitory effects on glioma cells, it has not been able to significantly improve the survival rate of patients with glioma (36). However, therapy using a combination of different drugs may be effective for gliomas (55). Da Ros et al (36) treated glioma cell lines U87, A172 and T98G with TMZ (100 and 200 µM) in combination with aldoxorubicin, a novel prodrug of doxorubicin (12 µM). The results showed that low concentrations of TMZ (100 µM) conferred no toxicity in any of the cell lines. However, higher concentrations of TMZ (200 µM) were shown to be toxic to U87 and A172 cells whereas T98G cells remained TMZ-resistant (36). Aldoxorubicin could significantly reduce the cell viability of all cell lines tested, where toxicity to T98G cells was shown to be more potent (36). Therefore, it was concluded that the addition of aldoxorubicin can enhance the killing effects of TMZ on TMZ-resistant glioma cells (36). TMZ combined with formononetin has a synergistic inhibitory effect on glioma cells (56). TMZ combined with pilocin and formononetin can inhibit the growth of glioma cells in vitro and tumor growth in vivo (57). In addition, TMZ combined with proteasome inhibitors also have certain antitumor effects. TMZ combined with alphatinib (EGFR inhibitor) has an inhibitory effect on glioma in vivo and in vitro (58). TMZ combined with bortezomib (BTZ) (proteasome inhibitor) can enhance the sensitivity of TMZ in the treatment of gliomas in vitro and in vivo (59). TMZ combined with amlotinib (a novel multi-target TKI) can synergistically inhibit the proliferation and angiogenesis of glioma cells and inhibit tumor growth in vitro (60). TMZ forms part of the standard chemotherapeutic strategy for the treatment of glioma. However, drug resistance to TMZ and toxic effects (myelosuppression and delayed thrombocytopenia) limit its efficacy, which highlights the importance of exploring the novel treatment options (61,62). Previous preclinical studies (6365) applied nanoparticles as carriers in an attempt to effectively deliver chemotherapeutic drugs to the glioma region by crossing the BBB, and minimize drug resistance (62). These nanocarriers can be functionalized by some molecules to cross the BBB and specifically target glioma cells. For example, Angiopep2 (A2) has brain-targeting properties, such that its modified polymeric counterpart can penetrate the BBB through receptor-mediated transport, which is widely applied to design nanocarriers (66). Polo-like kinase 1 (PLK1) serves a key role in cell cycle regulation, where its expression in glioma tissues was found to be significantly higher compared with that in corresponding normal brain tissues. Inhibition of PLK1 activity can lead to cell cycle arrest and increase apoptosis of glioma cells. Shi et al (16) previously prepared a polymer micelle modified by A2 (A2PEC). These micelles in turn encapsulated TMZ and small interfering RNA (siRNA) targeting PLK1 (TMZ-A2PEC/siPLK), which were used in U87 and LN-299 glioma cells. The results of these previous in vitro experiments showed that TMZ-A2PEC/siPLK could effectively reduce cell viability to a greater extent compared with that mediated by TMZ alone. In addition, results from in vivo experiments revealed that TMZ-A2PEC/siPLK could significantly prolong the survival time of mice injected with U87 cells (47.5 days). The degree of weight loss was also the slowest in the TMZ-A2PEC/siPLK, which also exhibited the least systemic toxic effects. TMZ-A2PEC/siPLK is an option for glioma therapy because it can reverse drug resistance while minimizing the toxicity of TMZ (16). This strategy of drug co-delivery using nanocarriers and molecular targeting has the potential of reversing chemotherapeutic drug resistance, reducing toxic effects and improving treatment efficacy.

Table I.

Preclinical studies of anti-glioma chemotherapeutics.

Table I.

Preclinical studies of anti-glioma chemotherapeutics.

Author (year)AgentIn vivo/In vitroCombination therapyTreatment effect(Refs.)
Wang et al, 2016TMZIn vitro-Inhibiting proliferation, migration and invasion(35)
Da Ros et al, 2018TMZIn vitroAldoxorubicinEnhancing the killing effect of TMZ on TMZ-resistant glioma cells(36)
Shi et al, 2020TMZBothPolymer micelleInhibiting cell viability and prolonging the survival time of U87 mice(16)
Hu et al, 2021TMZ-NF-κB and MGMT inhibitorsDownregulating MGMT and improving TMZ sensitivity(37)
Wu et al, 2021TMZIn vitroTalazoparibInhibiting the proliferation and downregulating MGMT and poly (ADP-ribose) polymerase(38)
Rahman et al, 2019TMZBothBortezomibInhibiting the proliferation, MGMT, MGMT mRNA and nuclear phosphorylation/activation p65. Prolonging the survival time of mice(39)
Rezaei et al, 2020BCNUIn vitromiR-181aInhibiting cell proliferation and migration. Promoting apoptosis(40)
Lu et al, 2016NimustineIn vitroHyperbaric oxygenInhibiting tumor growth and reducing the tumor volume(41)
Yi et al, 2019BCNUBothMetal nanoparticlesInhibiting proliferation and decreasing the survival rate. Targeting efficiency is higher(42)
Ashrafzadeh et al, 2020CisplatinBothOX26 monoclonal antibody and liposomesIncreasing the uptake of C6 cells. Improving the mean survival time and reducing toxicity(43)
Zhang et al, 2017CisplatinIn vitroNanoparticles and convection-enhanced deliveryThe distribution volume of the brain was higher and prolonging the survival time of rats(44)
Thakur et al, 2020DoxorubicinIn vitroExosomesInhibiting the proliferation(45)
Meng et al, 2019DoxorubicinBothNano-micelleInhibiting the proliferation and inducing apoptosis. Reducing the tumor volume and increasing drug accumulation(46)
Zhang et al, 2017DoxorubicinIn vivoLiposomes and vincristineReducing the tumor volume and prolonging the median survival time(27)
Park et al, 2016VincristineIn vitro-Inhibiting glioma cell proliferation and glioma angiogenesis(47)
Fu et al, 2019VincristineBothNanoparticlesIncreasing the toxic effect of vincristine. Reducing tumor and prolonging the mean survival time(48)
Wu et al, 2016VincristineBothSolid nano-lipid particles, NLCS and TMZThe inhibition effect of NLCS was the strongest and inhibiting tumor growth(49)
Koosha et al, 2017TopotecanIn vitroA966492 and radiationDecreasing the cell survival rate and increasing the radiation lethal effect(50)
Sharon and Rubinstein, 2021TopotecanIn vitroCaCl2 and PLGA microspheresDecreasing the relative survival rate of cells and increasing the toxic effect of topotecan(51)

[i] TMZ, temozolomide; MGMT, O6-methylguanine-DNA methyltransferase; NLCS, nano-lipid carriers; BCNU, carmustine.

Study on targeted therapy for reversing TMZ resistance

The unique stability and solubility of TMZ render it viable for oral administration and gives it the ability to pass through the BBB. It can be activated without liver metabolism and can spontaneously transform into the active alkylating agent monomethyl triazene 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MITC) under physiological conditions (67,68). The main mechanism of TMZ for treating glioma is to first deliver its methyl group to tumor cell DNA, causing DNA methylation and DNA damage in tumor cells. This in turn inhibits tumor cell proliferation, while inducing cell apoptosis (62,69). TMZ destroys the DNA of tumor cells by delivering the active methyl groups to O6 and N7 position of guanine and the N3 position of adenine to form cytotoxic O6-methylguanine (O6-MeG), N7-methylguanine (N7-MeG) and N3-methyladenine (N3-MeA) (70). By contrast, cytotoxicity induced by TMZ is mainly caused by O6-MeG. TMZ-resistant DNA repair systems mainly include O6-methylguanine-DNA methyltransferase (MGMT), mismatch repair (MMR) and base excision repair (BER) (Fig. 1) (62). MGMT is a DNA repair protein that removes the methyl group from O6-MeG and binds it to its own cysteine residue, so that the tumor cells survive (71,72). In the absence of MGMT expression, O6-MeG mismatches with thymine, where MMR removes thymine leaving behind the methylated guanine, which reduces the efficiency of DNA mismatch repair and produces double strand breaks, in turn inducing eventual cell death. BER can repair N7-MeG and N3-MeA so that the tumor cells survive (7375). MGMT is the most important factor for TMZ resistance in GBM and can be regulated by various factors, including transcription factors, epigenetic elements (such as methylation, phosphorylation, histone acetylation and microRNA expression from the MGMT promoter), the protein kinase A, and the MAPK/JNK and NF-κB signaling pathways (76). Both O6-benzylguanine (O6-BG) and O6-(4-bromophenyl) guanine (O6-BTG) are MGMT inhibitors. Although both held promise as a treatment option for glioma, they can cause damage to normal tissues, causing adverse events (71). Hu et al (37) revealed that receptor-interacting protein 2 (RIP2) could activate the NF-κB signaling pathway, upregulate the expression of MGMT and increase the resistance of glioma cells to TMZ. By using NF-κB and MGMT inhibitors combined with TMZ on TMZ-resistant glioma cell lines T98G and U87MG in addition to RIP2-overexpressing cells, it was found that MGMT expression was downregulated whereas the inhibition of NF-κB/MGMT signaling can improve TMZ sensitivity. The RIP2/NF-κB/MGMT signaling pathway serves an important role in mediating TMZ resistance. Poly (ADP-ribose) polymerase (PARP) is an enzyme that regulates BER. PARP1-mediated BER/single strand break repair is a key process for the repair of N7-MeG and N3-MeA. Wu et al (38) previously documented that the PARP inhibitor talazoparib (25 nM) significantly inhibited the proliferation of MGMT-positive glioma globular-forming cells induced by TMZ. In addition, the protein expression levels of MGMT and PARP activation induced by TMZ were decreased. PARP can regulate the activity of MGMT through BER, whereas PARP inhibitors can improve the sensitivity of TMZ for the treatment of gliomas. The in vitro results from a study by Rahman et al (39) demonstrated that pre-treatment with 10 nM 26S proteasome inhibitor BTZ combined with TMZ could significantly inhibit the proliferation of glioma cells while reducing the expression levels of MGMT, MGMT mRNA and nuclear phosphorylation/activation of the p65 subunit. Subsequent in vivo experiments revealed that BTZ + TMZ treatment could significantly reduce the tumor volume and prolong the survival time of the mice (the median survival time was 114 days). BTZ + TMZ was therefore proposed to consume MGMT and block NF-κB/p65 signaling transduction to improve the sensitivity of TMZ (39). Riluzole is a metabolic glutamate receptor 1 (mGluR1) inhibitor. It has been previously reported that riluzole can inhibit the progression of GBM by inhibiting the PI3K/AKT/mTOR signaling pathway. PI3K inhibitors can also inhibit the expression of MGMT by inhibiting the PI3K/AKT/NF-κB and mGluR1/PI3K/AKT/mTOR signaling pathways. TMZ combined with riluzole was found to significantly inhibit the proliferation of the MGMT-positive cell lines T98G and GL261, but not in the MGMT-negative cell line U87. In addition, riluzole was also able to downregulate MGMT expression induced by TMZ. TMZ combined with riluzole could significantly reduce the average maximum cross-sectional area and volume of the tumors in mice injected with GL261 cells, suggesting TMZ + riluzole as a potential treatment (77). The expression level of MGMT is associated with the efficacy of treatment. Overexpression of MGMT is an important mechanism underlying TMZ resistance. Understanding this mechanism while developing novel treatment methods would be beneficial for improving the sensitivity to TMZ.

Nitrosourea-based chemotherapy

Targeted therapy and other combinatorial therapy using nitrosourea-based chemotherapeutic drugs

Nitrosourea-based chemotherapeutic drugs, including nimustine (ACNU), carmustine (BCNU), lomustine (CCNU) and ranimustine can pass through the BBB. ACNU is a second-line chemotherapeutic agent for the treatment of gliomas (78,79). Nitrosourea-based chemotherapeutic agents act by inducing cytotoxicity in malignant gliomas, where they can induce tumor cell death and changes in biological behavior. These drugs mainly target tumor cell DNA by first alkylating the bases of tumor cell DNA, which then form inter-chain crosslinks. This causes high cytotoxicity, induces DNA double-strand break and prevents DNA replication and transcription to finally result in cell apoptosis and necrosis (80). Nitrosourea chemotherapeutic drugs have myelosuppression and hematological toxicity (80,81). Due to the limited efficacy of chemotherapeutic drugs when applied alone, previous studies that investigated the effects of multiple combination therapies revealed that the resultant efficacy is superior compared with that in chemotherapy alone (30,80,82). O6-alkylguanine-DNA alkyltransferase (AGT)/MGMT is the main component that determines the efficacy and drug resistance of nitrosourea. O6-BG is an inhibitor of AGT that can effectively inhibit the activity of AGT. By contrast, O6-BTG can exert superior inhibitory effects on AGT, and has since entered clinical trial testing, but it lacks a specific target and induces serious myelosuppressive toxicity (83,84). Tumor cell death is dependent on the inhibition of glycolysis. The glycolysis inhibitor 3-bromopyruvate combined with BCNU has been shown to significantly enhance the cytotoxicity of BCNU while reducing intracellular ATP and glutathione levels in human glioma cell lines SF763 and SF126. Glycolysis inhibitors are expected to become an effective agent for reversing nitrosourea resistance (84). Rezaei et al (40) previously treated U373 glioma cells with microRNA (miR or miRNA)-181a combined with BCNU. The results showed that miR-181a mediated downregulation of AKT1, suggesting that miRNA can inhibit glioma cell proliferation by regulating the PI3K/AKT signaling pathway. In addition, miR-181a significantly reduced the semi-inhibitory concentration of BCNU from 169.8 µM in BCNU alone to 83.25 µM in the combined treatment group. The combined use of miR-181a and BCNU was also shown to significantly inhibit cell migration compared with that in BCNU alone. In addition, miR-181a could potentiate apoptosis induced by BCNU (40). Hyperbaric oxygen is a non-invasive form of therapy that can inhibit glioma cell proliferation and inflammatory cell infiltration. Lu et al (41) used hyperbaric oxygen combined with ACNU to treat mice injected with the human glioma SU3 stem cells, which significantly inhibited tumor growth and reduced tumor volume, where the tumor inhibition rate was ≤76.29%. The tumor weight of the mice treated with combined therapy was found to be significantly lower compared with that in mice treated with either drug alone, suggestive of a synergistic effect. Subsequent tumor histopathological results showed that after hyperbaric oxygen combined with ACNU treatment, the degree of necrosis and inflammatory cell infiltration were reduced. However, toxicity associated with nitrosourea-based chemotherapy and resistance to nitrosourea are key factors that minimize their efficacy. To address the toxicity issue, Yi et al (42) used the synthesized BCNU and loaded them into metal nanoparticles prior to treating glioma U251 cells, which was found to inhibit proliferation while significantly decreasing its survival rate. In the mouse model, this nano-compound was shown to readily deliver the drugs to the brain without causing damage to the normal brain tissue. In addition, it tended to preferentially accumulate in glioma cell masses, to a greater degree compared with the accumulation of BCNU alone. The results of subsequent wound healing assays in vivo revealed that the synthesis of BCNU and metal nanoparticles is beneficial to wound tissue regeneration and promote wound healing, implicating them to be another potential treatment option (42). Nitrosourea chemotherapeutic drugs have been applied for the treatment of gliomas before the emergence of TMZ (81). Over the past decade, previous studies have shown that nitrosourea chemotherapy can be used for the remedial treatment of TMZ resistance (85).

Platinum chemotherapy

Platinum chemotherapeutic agents include cisplatin, carboplatin and oxaliplatin. It has been reported that the exposure of glioma cells to the platinum family of chemotherapeutic drugs can induce tumor cell death. The potential mechanism underlying this effect may be the induction of single-strand or double-strand breaks in the DNA (86). Cisplatin and carboplatin are broad-spectrum agents that cannot be taken orally. Instead, they need to be injected intravenously because they are not soluble in water and are not stable. In addition, they are polar macromolecules, meaning that they cannot pass through the BBB easily (87). This results in low antitumor efficacy, high risks of systemic toxicity and drug resistance. Cisplatin therapy can cause nephrotoxicity and gastrointestinal toxicity, while carboplatin therapy can cause myelosuppression and ototoxicity (88). After carboplatin and cisplatin are injected intravenously, the permeability of BBB to carboplatin and cisplatin is limited, leading to the uneven distribution of these drugs to the tumor area, where the antitumor effect is poor. However, although arterial infusion can greatly increase the accumulation of drugs in the tumor cell masses, it is considered to be highly toxic (89). To improve therapeutic efficacy and reduce systemic toxicity, chemotherapeutic drugs can be packaged into liposomes, peptide/protein conjugates, polymers, polymer micelles and nanoparticles (90). Transferrin receptor (TR) is a potential biological vehicle for drug delivery in the brain. Furthermore, OX26 is a mouse monoclonal antibody that can target TR in rats. Ashrafzadeh et al (43) previously packaged the OX26 monoclonal antibody into the targeted polyethylene glycol cisplatin liposomes (TPL-Cispt). Results from the cell uptake assay in vitro showed that TPL-Cispt delivery resulted in significantly higher cell uptake, specifically increasing uptake by C6 cells 1.43-fold. Subsequent results from in vivo experiments showed that the mean survival time (MST) of rats treated with TPL-Cispt was 45 days, which represents a 1.7-fold increase. In addition, the toxicity normally induced by cisplatin was shown to be reduced. Therefore, polyethylene glycol liposomes carrying cisplatin was concluded to improve the treatment efficacy of brain tumors with reduced toxicity. However, lipid nanoparticles are typically large in diameter and adhere to the extracellular matrix, meaning that they cannot penetrate brain tumors efficiently. Zhang et al (44) previously manufactured a type of brain-penetrating nanoparticles encapsulating cisplatin and delivered it by convection-enhanced delivery (CED). CED (Fig. 2) is a minimally invasive, locally targeted drug delivery method. Using stereotactic technology, the therapeutic agents in the catheter are directly injected into the tumor around the BBB to achieve the purpose of accurate targeted therapy (9193). The diffusion rate of brain-penetrating nanoparticles containing cisplatin in healthy rats and rats injected with F98 glioma cells was found to be significantly higher compared with that in rats treated with cisplatin alone (44). In addition, the distribution volume of brain-penetrating nanoparticles containing cisplatin in the brain was found to be 14 times higher compared with that in the cisplatin-alone group. After the brain-penetrating nanoparticles containing cisplatin and cisplatin alone were delivered separately through CED, the distribution volume of brain-penetrating nanoparticles containing cisplatin in the brain was found to be 29 times higher compared with that in the cisplatin-alone group. In terms of survival, the targeted delivery of brain-penetrating nanoparticles of cisplatin using CED can significantly prolong the survival time of rats with superior tolerance (44). In conclusion, although platinum-based chemotherapeutic agents are highly effective especially in vitro, the BBB and occurrence of systemic toxicity limit their efficacy in treating glioma, which require optimization using alternative drug delivery systems.

Other chemotherapy agents

Doxorubicin (DOX)

DOX is an anthracycline antibiotic chemotherapy agent and is one of the most extensively used antitumor drugs (94). Its main mechanism of action is by quickly entering the nuclei of tumor cells and inhibiting the proliferation of tumor cells by binding to DNA and blocking DNA replication (95,96). DOX has been found to inhibit the proliferation of glioma cells. After the glioma cells were treated with 10 and 100 nM of DOX for 7, 10 and 14 days, the cell survival rate was decreased in a dose- and time-dependent manner, which was the lowest at the dosage of 100 nM DOX for 14 days. However, DOX treatment combined with TMZ conferred no synergistic effects (97). DOX cannot pass through the BBB easily, which limits its use in gliomas. However, exosomes can cross the BBB and serve as a potential carrier for the delivery of chemotherapeutic drugs for glioma. Thakur et al (45) previously loaded DOX into exosomes derived from SF7761 glioma stem cells and U251 glioma cells using a microfluidic device, before treating SF7761 and U251 cells with DOX-containing exosomes. The results showed that DOX-containing exosomes can inhibit the proliferation of cells more effectively compared with that treated with DOX alone. Over the past number of years, to improve the permeability of BBB to chemotherapeutic drugs, studies into novel drug delivery systems have accelerated. Meng et al (46) used a borneol-modified nano-micelle delivery system to encapsulate and deliver DOX. Results from proliferation experiments in vitro showed that borneol-modified DOX nano-micelles inhibited the proliferation and migration of C6 glioma cells while inducing C6 cell apoptosis to a higher degree, where the magnitude of these inhibitory effects was greater compared with those mediated by DOX alone. The results of tumor experiments in vivo revealed that borneol-modified DOX nano-micelles significantly reduced the tumor volume, bleeding and necrosis in mice compared with those treated with DOX alone. There were no clear side effects following measurements of the weight of the mice. In addition, borneol-modified DOX nano-micelles significantly improved the transport efficiency of DOX across the BBB, which was rapidly accumulated in the brain tissues. However, large doses or long-term use of DOX can cause cardiomyocyte toxicity, ultimately leading to heart failure. To minimize this toxic adverse effect, it has been proposed that DOX liposomes can be used for targeted delivery, where the combination of DOX liposomes with other drugs conferred superior antitumor activity (94,96). Vincristine can mediate cardioprotective effects against DOX-induced cardiomyocyte toxicity and chemical and hypoxic oxidative stress. T7 is a heptapeptide ligand of the transferrin receptor that can bypass the BBB and target glioma directly. DA7R is a D-peptide ligand of VEGF receptor 2 overexpressed on angiogenesis, which has exhibited promising homing characteristics towards glioma. Zhang et al (27) previously applied T7- and DA7R dipeptide-modified liposomes to co-deliver DOX and vincristine into mouse glioma tumors, which significantly reduced the tumor volume, reduced the tumor proliferation rate and significantly prolonged the median survival time (34 days). Although DOX confers anti-glioma effects, it cannot pass through BBB at its effective therapeutic dose range. Therefore, it is necessary to develop novel drug delivery systems into the brain to improve its efficacy (98,99).

Vincristine

Vincristine is a type of drug that functions by destroying the stability of microtubules and interferes with the metabolism of tumor cells by acting on the tubulin cytoskeleton of tumor cells (100). Therefore, anti-angiogenesis and antitumor activities (47) have been reported. Park et al (47) reported that vincristine can inhibit glioma cell proliferation in a dose-dependent manner while inhibiting glioma angiogenesis under hypoxic conditions, which was proposed to be mediated at least in part by the inhibition of hypoxia-inducible factor-1α (HIF-1α). Vincristine is a microtubule-targeting drug that is also commonly used in gliomas. Microtubule-associated protein 2 (MAP2) is a microtubule-stabilizing protein. Knocking down MAP2 expression can significantly inhibit the migration and survival of glioma cells in vitro, in addition to inducing apoptosis and increasing the sensitivity of glioma cells to vincristine (101). Vincristine has a large molecular weight and therefore cannot pass through the BBB easily, which can cause peripheral neuropathy and systemic toxicity (102). The existence of BBB and the blood-brain tumor barrier (BBTB) render the accurate targeting of chemotherapeutic drugs challenging. Fu et al (48) designed a peptide nanoparticle carrier dual-modified with T7 and reticulon 4 receptor (NGR) based on encapsulated solid lipid nanoparticles from red blood cells (T7/NGR-RBCSLNs) to encapsulate vincristine for the treatment of gliomas. T7 was found to penetrate the BBB and target glioma cells. NGR is a polypeptide ligand of CD13 that is overexpressed during angiogenesis and has demonstrated promising homing characteristics towards glioma. In addition, it can penetrate the BBTB and target glioma cells. The results of cytotoxicity testing in vitro showed that T7/NGR-RBCSLNs encapsulated with vincristine could significantly increase the toxic effects of vincristine on C6 cells. Subsequent tumor experiments in vivo found that the tumor in the T7/NGR-RBCSLNs-encapsulated vincristine group was significantly reduced, where the relative tumor inhibition rate was the highest and the MST was significantly prolonged (36 days). Vincristine combined with the double-targeting delivery (T7/NGR-RBCSLNs) showed the optimal anti-glioma effects in vivo and in vitro in the brain. The efficacy conferred by treatment with only a single chemotherapeutic drug is limited whereas treatment with a combination of drugs can improve efficacy without worsening systemic toxicity. Therefore, overcoming drug resistance using other drug delivery systems is required to enhance the efficacy of chemotherapy. Wu et al (49) used solid nano-lipid particles and nano-lipid carriers (NLCS) to enclose vincristine and TMZ. Subsequent results from the in vitro cytotoxicity assay showed that the inhibitory effect of NLCS-vincristine + TMZ on U87 glioma cells was the most potent, which was significantly higher compared with that mediated by either drug alone. The results of this previous tumor study in vivo showed that NLCS-encapsulated vincristine and TMZ significantly inhibited tumor growth, where the tumor inhibition rate was >80%. These results were consistent both in vivo and in vitro. This dual-drug administration provides a novel idea for the clinical intervention of glioma.

Topotecan

Topotecan is a water-soluble, semisynthetic camptothecin analog that has a small molecular weight and can pass through the BBB (103). It has been approved for use in different types of tumors as topoisomerase I inhibitors by Serwer et al (104). It is toxic to glial cells and relatively non-toxic to normal brain tissue (105). Topotecan can form stable topoisomerase I and DNA cleavage complexes in vivo and in vitro. During the process of DNA replication in tumor cells, topoisomerase I can be embedded in DNA, resulting in DNA damage and fragmentation, which finally promote the death of tumor cells (104). Topotecan has significant reported antitumor effects according to various preclinical studies (106). Small ubiquitin-like modifier (SUMO) modification is a unique form of protein post-translational modification that is key for the maintenance of cell function under stress or adverse conditions. However, blocking SUMO-1-3 binding in glioma cells can inhibit DNA synthesis, proliferation and survival of glioma cells. Topotecan (1 and 10 µM) significantly inhibited SUMO binding in glioma cells, decreased cyclin-dependent kinase 6 and HIF-1α expression and changed the cell cycle and metabolic profile (103). At present, the most important strategy used to treat glioma is to maximize surgical resection combined with radiotherapy and chemotherapy. However, the adverse effects caused by radiotherapy and chemotherapy are typically severe. Radiosensitization drugs can improve the efficacy of radiotherapy and reduce its side effects. Koosha et al (50) reported the radiosensitization effects of topotecan combined with A966492 on U87 glioma cell spheres. A966492 is a new type of PARP inhibitor, that can cross the BBB. Compared with radiation alone, topotecan combined with A966492 and 6 mV X-ray radiation significantly increased the lethal effects of radiation on U87 glioma cell spheres. Chemotherapeutic drugs can induce systemic toxicity, while local chemotherapy can reduce systemic exposure. Sharon and Rubinstein (51) divided the dose of topotecan into three equal parts and changed it daily during the 72-h incubation with U87 glioma cells to simulate slow and continuous administration. The relative survival rate of cells was significantly decreased, from 35 to 7%. After CaCl2 was added, the relative survival rate of cells was decreased even further, significantly from 28 to 1.9%. Topotecan mediated synergistic effects with CaCl2. Co-loading of CaCl2 into topotecan poly (lactic-co-glycolic acid) microspheres increased the toxic effects of topotecan on U87 cells, where the cell viability decreased from 72 to 27%. Topotecan has not been routinely used in clinical practice due to toxicity and related pharmacokinetic shortcomings. Drug delivery systems, such as poly (lactic-co-glycolic acid) microspheres, are increasingly being used as the blueprint to develop novel cancer treatments, because this technology can regulate the biological distribution and target accumulation of chemotherapeutic drugs, thereby reducing their toxicity.

Advances in the clinical application of anti-glioma chemotherapeutics

In recent years, patients with glioma who received a single chemotherapy regimen are particularly at risk of drug resistance and relapse. In a previous clinical study of 27 patients treated with TMZ combined with cisplatin, the progression-free survival (PFS) was improved (107). In another clinical trial, TMZ combined with bevacizumab was used to treat 30 patients with recurrent GBM, which yielded a median overall survival (OS) of 51 weeks and a PFS of 52% at 6 months, suggesting that this treatment may be effective for patients with recurrent GBM (108). Herrlinger et al (109) previously compared the effects of CCNU combined with TMZ and standard TMZ therapy on the survival time of patients with GBM and MGMT methylation. The results showed that the OS and median survival time in the CCNU + TMZ treatment group were significantly higher compared with those in the standard TMZ group (109). However, in the study performed by Kim et al (110), the efficacy of procarbazine combined with CCNU for the treatment of patients with recurrent GBM and MGMT methylation was not optimistic due to its toxicity. Although the combination of chemotherapeutic drugs together does exert certain curative effects, drug resistance and toxicity limit efficacy. Therefore, additional prospective studies are required to evaluate the efficacy of various combinations of chemotherapeutic drugs for the treatment of gliomas. A number of clinical trials (Table II) that are evaluating the targeted treatment of GBM using chemotherapeutic drugs and other combination therapies can be found in https://clinicaltrials.gov. Amongst these studies, one of them is the evaluation of the combination of O6-BG and TMZ for the treatment of newly diagnosed GBM (ClinicalTrials.gov identifier no. NCT00272870).

Table II.

Clinical trials of anti-glioma chemotherapy drugs.

Table II.

Clinical trials of anti-glioma chemotherapy drugs.

Clinical trials numberStatusAgentPhaseCombination therapyResearch purposes
NCT00272870TerminatedTMZIO6 Benzyl guanineOvercoming TMZ resistance and hematologic toxicity
NCT05052957Not yetTMZIIO6 Benzyl guanineTreatment
recruitingCarmustine
NCT00687765CompletedTMZI and IIBSI-201 (PARP-1 inhibitor)Determining the maximum tolerated dose of BSI-201 and evaluating efficacy
NCT03914742RecruitingTMZI and IIBGB-290 (PARP inhibitor)Treatment
NCT03749187RecruitingTMZIBGB-290 (PARP inhibitor)Evaluating the side effects and the optimal dose
NCT00994071CompletedTMZIABT-888 (PARP inhibitor)Treatment
NCT01644955CompletedCarboplatinIConvection-enhanced deliveryTreatment and assessing maximum tolerated dose and toxic effects
NCT03603379CompletedDoxorubicinI Anti-EGFR-immunoliposomes loaded with doxorubicin (C225-ILs-dox) Pharmacokinetics
NCT00944801CompletedDoxorubicinI and IIPegylated liposomalTreatment
NCT02766699UnknowDoxorubicinI EGFR(V)-EDV-DoxAssessment of safety, tolerability and immunogenicity
NCT02333513UnknowVincristine--Treatment
NCT03927274RecruitingTopotecanIConvection-enhanced deliveryAssessing safety and tolerability
NCT02278510CompletedTopotecanIGadolinium DTPA and convection-enhanced deliveryTreatment
NCT03154996CompletedTopotecanIGadolinium and convection-enhanced deliveryTreatment

[i] PARP, Poly (ADP-ribose) polymerase; TMZ, temozolomide.

Conclusion

Glioma is the most common malignancy in the central nervous system with high recurrence rates and poor prognosis. Drug resistance is the main complication obstructing glioma chemotherapy and provides a significant challenge for improving the therapeutic effects. The development of novel agents and the use of drug resistance induction media and molecular signaling pathway inhibitors are some of the methods of overcoming the resistance of glioma to chemotherapeutic drugs. The combined use of drugs and nanoparticles along with other carriers has been reported to reduce drug resistance and toxicity. Therefore, it is of importance to develop novel drug delivery methods for improving drug solubility, prolonging circulation time, enhancing the targeted effects and improving the efficacy of chemotherapeutic drugs for clinical application. As information is being constantly accumulated regarding the physiology of glioma, the comprehensive application of multiple treatment methods for glioma and the treatment mechanism of chemotherapy drugs, chemotherapeutic agents serve an increasingly important role for the treatment of glioma.

Acknowledgements

Not applicable.

Funding

The present study was supported by the National Natural Science Foundation of China (grant no. 12071075), the Guangdong Medical Research Fund (grant no. A2020278) and Summit Program of Foshan (grant no. 2019C016).

Availability of data and materials

Not applicable.

Authors' contributions

YSZ wrote the manuscript. YSZ, NC and LCW collected and analyzed data. JBH and WW critically revised the manuscript. All authors read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P and Ellison DW: The 2016 world health organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 131:803–820. 2016. View Article : Google Scholar : PubMed/NCBI

2 

Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, et al: The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol. 23:1231–1251. 2021. View Article : Google Scholar : PubMed/NCBI

3 

Tan AC, Ashley DM, López GY, Malinzak M, Friedman HS and Khasraw M: Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 70:299–312. 2020. View Article : Google Scholar : PubMed/NCBI

4 

Nayak L and Reardon DA: High-grade gliomas. Continuum (Minneap Minn). 23:1548–1563. 2017.PubMed/NCBI

5 

Miller KD, Ostrom QT, Kruchko C, Patil N, Tihan T, Cioffi G, Fuchs HE, Waite KA, Jemal A, Siegel RL and Barnholtz-Sloan JS: Brain and other central nervous system tumor statistics, 2021. CA Cancer J Clin. 71:381–406. 2021. View Article : Google Scholar : PubMed/NCBI

6 

Han T, Zuo Z, Qu M, Zhou Y, Li Q and Wang H: Comprehensive analysis of inflammatory response-related genes, and prognosis and immune infiltration in patients with low-grade glioma. Front Pharmacol. 12:7489932021. View Article : Google Scholar : PubMed/NCBI

7 

Ogino H, Taylor JW, Nejo T, Gibson D, Watchmaker PB, Okada K, Saijo A, Tedesco MR, Shai A, Wong CM, et al: Randomized trial of neoadjuvant vaccination with tumor-cell lysate induces T cell response in low-grade gliomas. J Clin Invest. 132:e1512392022. View Article : Google Scholar : PubMed/NCBI

8 

Choi S, Yu Y, Grimmer MR, Wahl M, Chang SM and Costello JF: Temozolomide-associated hypermutation in gliomas. Neuro Oncol. 20:1300–1309. 2018. View Article : Google Scholar : PubMed/NCBI

9 

Faulkner H, Arnaout O, Hoshide R, Young IM, Yeung JT, Sughrue ME and Teo C: The surgical resection of brainstem glioma: Outcomes and prognostic factors. World Neurosurg. 146:e639–e650. 2021. View Article : Google Scholar : PubMed/NCBI

10 

Dong CY, Hong S, Zheng DW, Huang QX, Liu FS, Zhong ZL and Zhang XZ: Multifunctionalized gold sub-nanometer particles for sensitizing radiotherapy against glioblastoma. Small. 17:e20065822021. View Article : Google Scholar : PubMed/NCBI

11 

Poon MTC, Sudlow CLM, Figueroa JD and Brennan PM: Longer-term (≥2 years) survival in patients with glioblastoma in population-based studies pre- and post-2005: A systematic review and meta-analysis. Sci Rep. 10:116222020. View Article : Google Scholar : PubMed/NCBI

12 

Wang Y, Jiang Y, Wei D, Singh P, Yu Y, Lee T, Zhang L, Mandl HK, Piotrowski-Daspit AS, Chen X, et al: Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance. Nat Biomed Eng. 5:1048–1058. 2021. View Article : Google Scholar : PubMed/NCBI

13 

Yang K, Wu Z, Zhang H, Zhang N, Wu W, Wang Z, Dai Z, Zhang X, Zhang L, Peng Y, et al: Glioma targeted therapy: Insight into future of molecular approaches. Mol Cancer. 21:392022. View Article : Google Scholar : PubMed/NCBI

14 

Goodenberger ML and Jenkins RB: Genetics of adult glioma. Cancer Genet. 205:613–621. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Carrillo JA and Munoz CA: Alternative chemotherapeutic agents: Nitrosoureas, cisplatin, irinotecan. Neurosurg Clin N Am. 23297–306. (ix)2012. View Article : Google Scholar : PubMed/NCBI

16 

Shi H, Sun S, Xu H, Zhao Z, Han Z, Jia J, Wu D, Lu J, Liu H and Yu R: Combined delivery of temozolomide and siPLK1 using targeted nanoparticles to enhance temozolomide sensitivity in glioma. Int J Nanomedicine. 15:3347–3362. 2020. View Article : Google Scholar : PubMed/NCBI

17 

Mehta S and Lo Cascio C: Developmentally regulated signaling pathways in glioma invasion. Cell Mol Life Sci. 75:385–402. 2018. View Article : Google Scholar : PubMed/NCBI

18 

Zhao M, van Straten D, Broekman MLD, Préat V and Schiffelers RM: Nanocarrier-based drug combination therapy for glioblastoma. Theranostics. 10:1355–1372. 2020. View Article : Google Scholar : PubMed/NCBI

19 

Haumann R, Videira JC, Kaspers GJL, van Vuurden DG and Hulleman E: Overview of current drug delivery methods across the blood-brain barrier for the treatment of primary brain tumors. CNS Drugs. 34:1121–1131. 2020. View Article : Google Scholar : PubMed/NCBI

20 

Xu Y, Yang X, Mei S, Sun Y and Li J: Acquisition of temozolomide resistance by the rat C6 glioma cell line increases cell migration and side population phenotype. Oncol Rep. 42:2355–2362. 2019.PubMed/NCBI

21 

Liu S, Shi W, Zhao Q, Zheng Z, Liu Z, Meng L, Dong L and Jiang X: Progress and prospect in tumor treating fields treatment of glioblastoma. Biomed Pharmacother. 141:1118102021. View Article : Google Scholar : PubMed/NCBI

22 

Velásquez C, Mansouri S, Mora C, Nassiri F, Suppiah S, Martino J, Zadeh G and Fernández-Luna JL: Molecular and clinical insights into the invasive capacity of glioblastoma cells. J Oncol. 2019:17407632019. View Article : Google Scholar : PubMed/NCBI

23 

Muir M, Gopakumar S, Traylor J, Lee S and Rao G: Glioblastoma multiforme: Novel therapeutic targets. Expert Opin Ther Targets. 24:605–614. 2020. View Article : Google Scholar : PubMed/NCBI

24 

Cheng F and Guo D: MET in glioma: Signaling pathways and targeted therapies. J Exp Clin Cancer Res. 38:2702019. View Article : Google Scholar : PubMed/NCBI

25 

Desjardins A, Rich JN, Quinn JA, Vredenburgh J, Gururangan S, Sathornsumetee S, Reardon DA, Friedman AH, Bigner DD and Friedman HS: Chemotherapy and novel therapeutic approaches in malignant glioma. Front Biosci. 10:2645–2668. 2005. View Article : Google Scholar : PubMed/NCBI

26 

Lapointe S, Perry A and Butowski NA: Primary brain tumours in adults. Lancet. 392:432–446. 2018. View Article : Google Scholar : PubMed/NCBI

27 

Zhang Y, Zhai M, Chen Z, Han X, Yu F, Li Z, Xie X, Han C, Yu L, Yang Y and Mei X: Dual-modified liposome codelivery of doxorubicin and vincristine improve targeting and therapeutic efficacy of glioma. Drug Deliv. 24:1045–1055. 2017. View Article : Google Scholar : PubMed/NCBI

28 

d'Angelo M, Castelli V, Benedetti E, Antonosante A, Catanesi M, Dominguez-Benot R, Pitari G, Ippoliti R and Cimini A: Theranostic nanomedicine for malignant gliomas. Front Bioeng Biotechnol. 7:3252019. View Article : Google Scholar : PubMed/NCBI

29 

Brandes AA, Bartolotti M, Tosoni A and Franceschi E: Nitrosoureas in the management of malignant gliomas. Curr Neurol Neurosci Rep. 16:132016. View Article : Google Scholar : PubMed/NCBI

30 

Stupp R: Drug development for glioma: Are we repeating the same mistakes? Lancet Oncol. 20:10–12. 2019. View Article : Google Scholar : PubMed/NCBI

31 

Yu Y, Wang L, Han J, Wang A, Chu L, Xi X, Kan R, Sha C and Sun K: Synthesis and characterization of a series of temozolomide esters and its anti-glioma study. J Pharm Sci. 110:3431–3438. 2021. View Article : Google Scholar : PubMed/NCBI

32 

Karachi A, Dastmalchi F, Mitchell DA and Rahman M: Temozolomide for immunomodulation in the treatment of glioblastoma. Neuro Oncol. 20:1566–1572. 2018. View Article : Google Scholar : PubMed/NCBI

33 

Cao H, Li X, Wang F, Zhang Y, Xiong Y and Yang Q: Phytochemical-mediated glioma targeted treatment: Drug resistance and novel delivery systems. Curr Med Chem. 27:599–629. 2020. View Article : Google Scholar : PubMed/NCBI

34 

Mirabdaly S, Elieh Ali Komi D, Shakiba Y, Moini A and Kiani A: Effects of temozolomide on U87MG glioblastoma cell expression of CXCR4, MMP2, MMP9, VEGF, anti-proliferatory cytotoxic and apoptotic properties. Mol Biol Rep. 47:1187–1197. 2020. View Article : Google Scholar : PubMed/NCBI

35 

Wang Y, Gao S, Wang W and Liang J: Temozolomide inhibits cellular growth and motility via targeting ERK signaling in glioma C6 cells. Mol Med Rep. 14:5732–5738. 2016. View Article : Google Scholar : PubMed/NCBI

36 

Da Ros M, Iorio AL, De Gregorio V, Fantappiè O, Laffi G, de Martino M, Pisano C, Genitori L and Sardi I: Aldoxorubicin and temozolomide combination in a xenograft mice model of human glioblastoma. Oncotarget. 9:34935–34944. 2018. View Article : Google Scholar : PubMed/NCBI

37 

Hu YH, Jiao BH, Wang CY and Wu JL: Regulation of temozolomide resistance in glioma cells via the RIP2/NF-κB/MGMT pathway. CNS Neurosci Ther. 27:552–563. 2021. View Article : Google Scholar : PubMed/NCBI

38 

Wu S, Li X, Gao F, de Groot JF, Koul D and Yung WKA: PARP-mediated PARylation of MGMT is critical to promote repair of temozolomide-induced O6-methylguanine DNA damage in glioblastoma. Neuro Oncol. 23:920–931. 2021. View Article : Google Scholar : PubMed/NCBI

39 

Rahman MA, Gras Navarro A, Brekke J, Engelsen A, Bindesbøll C, Sarowar S, Bahador M, Bifulco E, Goplen D, Waha A, et al: Bortezomib administered prior to temozolomide depletes MGMT, chemosensitizes glioblastoma with unmethylated MGMT promoter and prolongs animal survival. Br J Cancer. 121:545–555. 2019. View Article : Google Scholar : PubMed/NCBI

40 

Rezaei T, Hejazi M, Mansoori B, Mohammadi A, Amini M, Mosafer J, Rezaei S, Mokhtarzadeh A and Baradaran B: microRNA-181a mediates the chemo-sensitivity of glioblastoma to carmustine and regulates cell proliferation, migration, and apoptosis. Eur J Pharmacol. 888:1734832020. View Article : Google Scholar : PubMed/NCBI

41 

Lu Z, Ma J, Liu B, Dai C, Xie T, Ma X, Li M, Dong J, Lan Q and Huang Q: Hyperbaric oxygen therapy sensitizes nimustine treatment for glioma in mice. Cancer Med. 5:3147–3155. 2016. View Article : Google Scholar : PubMed/NCBI

42 

Yi S, Yang F, Jie C and Zhang G: A novel strategy to the formulation of carmustine and bioactive nanoparticles co-loaded PLGA biocomposite spheres for targeting drug delivery to glioma treatment and nursing care. Artif Cells Nanomed Biotechnol. 47:3438–3447. 2019. View Article : Google Scholar : PubMed/NCBI

43 

Ashrafzadeh MS, Akbarzadeh A, Heydarinasab A and Ardjmand M: In vivo glioblastoma therapy using targeted liposomal cisplatin. Int J Nanomedicine. 15:7035–7049. 2020. View Article : Google Scholar : PubMed/NCBI

44 

Zhang C, Nance EA, Mastorakos P, Chisholm J, Berry S, Eberhart C, Tyler B, Brem H, Suk JS and Hanes J: Convection enhanced delivery of cisplatin-loaded brain penetrating nanoparticles cures malignant glioma in rats. J Control Release. 263:112–119. 2017. View Article : Google Scholar : PubMed/NCBI

45 

Thakur A, Sidu RK, Zou H, Alam MK, Yang M and Lee Y: Inhibition of glioma cells' proliferation by doxorubicin-loaded exosomes via microfluidics. Int J Nanomedicine. 15:8331–8343. 2020. View Article : Google Scholar : PubMed/NCBI

46 

Meng L, Chu X, Xing H, Liu X, Xin X, Chen L, Jin M, Guan Y, Huang W and Gao Z: Improving glioblastoma therapeutic outcomes via doxorubicin-loaded nanomicelles modified with borneol. Int J Pharm. 567:1184852019. View Article : Google Scholar : PubMed/NCBI

47 

Park KJ, Yu MO, Park DH, Park JY, Chung YG and Kang SH: Role of vincristine in the inhibition of angiogenesis in glioblastoma. Neurol Res. 38:871–879. 2016. View Article : Google Scholar : PubMed/NCBI

48 

Fu S, Liang M, Wang Y, Cui L, Gao C, Chu X, Liu Q, Feng Y, Gong W, Yang M, et al: Dual-modified novel biomimetic nanocarriers improve targeting and therapeutic efficacy in glioma. ACS Appl Mater Interfaces. 11:1841–1854. 2019. View Article : Google Scholar : PubMed/NCBI

49 

Wu M, Fan Y, Lv S, Xiao B, Ye M and Zhu X: Vincristine and temozolomide combined chemotherapy for the treatment of glioma: A comparison of solid lipid nanoparticles and nanostructured lipid carriers for dual drugs delivery. Drug Deliv. 23:2720–2725. 2016. View Article : Google Scholar : PubMed/NCBI

50 

Koosha F, Neshasteh-Riz A, Takavar A, Eyvazzadeh N, Mazaheri Z, Eynali S and Mousavi M: The combination of A-966492 and Topotecan for effective radiosensitization on glioblastoma spheroids. Biochem Biophys Res Commun. 491:1092–1097. 2017. View Article : Google Scholar : PubMed/NCBI

51 

Sharon GR and Rubinstein A: Controlling the release rate of topotecan from PLGA spheres and increasing its cytotoxicity towards glioblastoma cells by co-loading with calcium chloride. Int J Pharm. 602:1206162021. View Article : Google Scholar : PubMed/NCBI

52 

Kim MM, Umemura Y and Leung D: Bevacizumab and glioblastoma: Past, present, and future directions. Cancer J. 24:180–186. 2018. View Article : Google Scholar : PubMed/NCBI

53 

Sonoda Y, Kanamori M, Deen DF, Cheng SY, Berger MS and Pieper RO: Overexpression of vascular endothelial growth factor isoforms drives oxygenation and growth but not progression to glioblastoma multiforme in a human model of gliomagenesis. Cancer Res. 63:1962–1968. 2003.PubMed/NCBI

54 

Grossman R, Brastianos H, Blakeley JO, Mangraviti A, Lal B, Zadnik P, Hwang L, Wicks RT, Goodwin RC, Brem H and Tyler B: Combination of anti-VEGF therapy and temozolomide in two experimental human glioma models. J Neurooncol. 116:59–65. 2014. View Article : Google Scholar : PubMed/NCBI

55 

Zhang R, Saito R, Shibahara I, Sugiyama S, Kanamori M, Sonoda Y and Tominaga T: Temozolomide reverses doxorubicin resistance by inhibiting P-glycoprotein in malignant glioma cells. J Neurooncol. 126:235–242. 2016. View Article : Google Scholar : PubMed/NCBI

56 

Zhang X, Ni Q, Wang Y, Fan H and Li Y: Synergistic anticancer effects of formononetin and temozolomide on glioma C6 cells. Biol Pharm Bull. 41:1194–1202. 2018. View Article : Google Scholar : PubMed/NCBI

57 

Ni Q, Fan Y, Zhang X, Fan H and Li Y: In vitro and in vivo study on glioma treatment enhancement by combining temozolomide with calycosin and formononetin. J Ethnopharmacol. 242:1116992019. View Article : Google Scholar : PubMed/NCBI

58 

Vengoji R, Macha MA, Nimmakayala RK, Rachagani S, Siddiqui JA, Mallya K, Gorantla S, Jain M, Ponnusamy MP, Batra SK and Shonka N: Afatinib and temozolomide combination inhibits tumorigenesis by targeting EGFRvIII-cMet signaling in glioblastoma cells. J Exp Clin Cancer Res. 38:2662019. View Article : Google Scholar : PubMed/NCBI

59 

Tang JH, Yang L, Chen JX, Li QR, Zhu LR, Xu QF, Huang GH, Zhang ZX, Xiang Y, Du L, et al: Bortezomib inhibits growth and sensitizes glioma to temozolomide (TMZ) via down-regulating the FOXM1-survivin axis. Cancer Commun (Lond). 39:812019. View Article : Google Scholar : PubMed/NCBI

60 

Xu P, Wang H, Pan H, Chen J and Deng C: Anlotinib combined with temozolomide suppresses glioblastoma growth via mediation of JAK2/STAT3 signaling pathway. Cancer Chemother Pharmacol. 89:183–196. 2022. View Article : Google Scholar : PubMed/NCBI

61 

Thomas AA and Rauschkolb PK: Tumor treating fields for glioblastoma: Should it or will it ever be adopted? Curr Opin Neurol. 32:857–863. 2019. View Article : Google Scholar : PubMed/NCBI

62 

Ortiz R, Perazzoli G, Cabeza L, Jimenez-Luna C, Luque R, Prados J and Melguizo C: Temozolomide: An updated overview of resistance mechanisms, nanotechnology advances and clinical applications. Curr Neuropharmacol. 19:513–537. 2021. View Article : Google Scholar : PubMed/NCBI

63 

Peng Y, Huang J, Xiao H, Wu T and Shuai X: Codelivery of temozolomide and siRNA with polymeric nanocarrier for effective glioma treatment. Int J Nanomedicine. 13:3467–3480. 2018. View Article : Google Scholar : PubMed/NCBI

64 

Song S, Mao G, Du J and Zhu X: Novel RGD containing, temozolomide-loading nanostructured lipid carriers for glioblastoma multiforme chemotherapy. Drug Deliv. 23:1404–1408. 2016. View Article : Google Scholar : PubMed/NCBI

65 

Afzalipour R, Khoei S, Khoee S, Shirvalilou S, Jamali Raoufi N, Motevalian M and Karimi MR: Dual-targeting temozolomide loaded in folate-conjugated magnetic triblock copolymer nanoparticles to improve the therapeutic efficiency of rat brain gliomas. ACS Biomater Sci Eng. 5:6000–6011. 2019. View Article : Google Scholar : PubMed/NCBI

66 

Costagliola di Polidoro A, Zambito G, Haeck J, Mezzanotte L, Lamfers M, Netti PA and Torino E: Theranostic design of angiopep-2 conjugated hyaluronic acid nanoparticles (Thera-ANG-cHANPs) for dual targeting and boosted imaging of glioma cells. Cancers (Basel). 13:5032021. View Article : Google Scholar : PubMed/NCBI

67 

Yang Z, Wei D, Dai X, Stevens MFG, Bradshaw TD, Luo Y and Zhang J: C8-substituted imidazotetrazine analogs overcome temozolomide resistance by inducing DNA adducts and DNA damage. Front Oncol. 9:4852019. View Article : Google Scholar : PubMed/NCBI

68 

Hotchkiss KM and Sampson JH: Temozolomide treatment outcomes and immunotherapy efficacy in brain tumor. J Neurooncol. 151:55–62. 2021. View Article : Google Scholar : PubMed/NCBI

69 

Sorribes IC, Handelman SK and Jain HV: Mitigating temozolomide resistance in glioblastoma via DNA damage-repair inhibition. J R Soc Interface. 17:201907222020. View Article : Google Scholar : PubMed/NCBI

70 

Butler M, Pongor L, Su YT, Xi L, Raffeld M, Quezado M, Trepel J, Aldape K, Pommier Y and Wu J: MGMT status as a clinical biomarker in glioblastoma. Trends Cancer. 6:380–391. 2020. View Article : Google Scholar : PubMed/NCBI

71 

Yu W, Zhang L, Wei Q and Shao A: O6-methylguanine-DNA methyltransferase (MGMT): Challenges and new opportunities in glioma chemotherapy. Front Oncol. 9:15472020. View Article : Google Scholar : PubMed/NCBI

72 

Lang F, Liu Y, Chou FJ and Yang C: Genotoxic therapy and resistance mechanism in gliomas. Pharmacol Ther. 228:1079222021. View Article : Google Scholar : PubMed/NCBI

73 

Daniel P, Sabri S, Chaddad A, Meehan B, Jean-Claude B, Rak J and Abdulkarim BS: Temozolomide induced hypermutation in glioma: Evolutionary mechanisms and therapeutic opportunities. Front Oncol. 9:412019. View Article : Google Scholar : PubMed/NCBI

74 

Tomar MS, Kumar A, Srivastava C and Shrivastava A: Elucidating the mechanisms of temozolomide resistance in gliomas and the strategies to overcome the resistance. Biochim Biophys Acta Rev Cancer. 1876:1886162021. View Article : Google Scholar : PubMed/NCBI

75 

Ohba S, Yamashiro K and Hirose Y: Inhibition of DNA repair in combination with temozolomide or dianhydrogalactiol overcomes temozolomide-resistant glioma cells. Cancers (Basel). 13:25702021. View Article : Google Scholar : PubMed/NCBI

76 

Liu Y, Du Z, Xu Z, Jin T, Xu K, Huang M, Wang S, Zheng Y, Liu M and Xu H: Overexpressed GNA13 induces temozolomide sensitization via down-regulating MGMT and p-RELA in glioma. Am J Transl Res. 13:11413–11426. 2021.PubMed/NCBI

77 

Yamada T, Tsuji S, Nakamura S, Egashira Y, Shimazawa M, Nakayama N, Yano H, Iwama T and Hara H: Riluzole enhances the antitumor effects of temozolomide via suppression of MGMT expression in glioblastoma. J Neurosurg. 134:701–710. 2020. View Article : Google Scholar : PubMed/NCBI

78 

Kaina B and Christmann M: DNA repair in personalized brain cancer therapy with temozolomide and nitrosoureas. DNA Repair (Amst). 78:128–141. 2019. View Article : Google Scholar : PubMed/NCBI

79 

Berte N, Piée-Staffa A, Piecha N, Wang M, Borgmann K, Kaina B and Nikolova T: Targeting homologous recombination by pharmacological inhibitors enhances the killing response of glioblastoma cells treated with alkylating drugs. Mol Cancer Ther. 15:2665–2678. 2016. View Article : Google Scholar : PubMed/NCBI

80 

Weller M and Le Rhun E: How did lomustine become standard of care in recurrent glioblastoma? Cancer Treat Rev. 87:1020292020. View Article : Google Scholar : PubMed/NCBI

81 

Lombardi G, Farina P, Della Puppa A, Cecchin D, Pambuku A, Bellu L and Zagonel V: An overview of fotemustine in high-grade gliomas: From single agent to association with bevacizumab. Biomed Res Int. 2014:6985422014. View Article : Google Scholar : PubMed/NCBI

82 

Rudà R, Touat M and Soffietti R: Is chemotherapy alone an option as initial treatment for low-grade oligodendrogliomas? Curr Opin Neurol. 33:707–715. 2020. View Article : Google Scholar : PubMed/NCBI

83 

Ge Y, Lai X, Li J, Yu R, Zhuang Z, Sun G, Cui X, Zhang N, Zhao L, Upadhyaya P and Zhong R: NBGNU: A hypoxia-activated tripartite combi-nitrosourea prodrug overcoming AGT-mediated chemoresistance. Future Med Chem. 11:269–284. 2019. View Article : Google Scholar : PubMed/NCBI

84 

Sun X, Sun G, Huang Y, Zhang S, Tang X, Zhang N, Zhao L, Zhong R and Peng Y: Glycolytic inhibition by 3-bromopyruvate increases the cytotoxic effects of chloroethylnitrosoureas to human glioma cells and the DNA interstrand cross-links formation. Toxicology. 435:1524132020. View Article : Google Scholar : PubMed/NCBI

85 

Yamamuro S, Takahashi M, Satomi K, Sasaki N, Kobayashi T, Uchida E, Kawauchi D, Nakano T, Fujii T, Narita Y, et al: Lomustine and nimustine exert efficient antitumor effects against glioblastoma models with acquired temozolomide resistance. Cancer Sci. 112:4736–4747. 2021. View Article : Google Scholar : PubMed/NCBI

86 

Rottenberg S, Disler C and Perego P: The rediscovery of platinum-based cancer therapy. Nat Rev Cancer. 21:37–50. 2021. View Article : Google Scholar : PubMed/NCBI

87 

Yang W, Barth RF, Huo T, Nakkula RJ, Weldon M, Gupta N, Agius L and Grecula JC: Radiation therapy combined with intracerebral administration of carboplatin for the treatment of brain tumors. Radiat Oncol. 9:252014. View Article : Google Scholar : PubMed/NCBI

88 

Shi M, Fortin D, Sanche L and Paquette B: Convection-enhance-ment delivery of platinum-based drugs and Lipoplatin(TM) to optimize the concomitant effect with radiotherapy in F98 glioma rat model. Invest New Drugs. 33:555–563. 2015. View Article : Google Scholar : PubMed/NCBI

89 

Charest G, Sanche L, Fortin D, Mathieu D and Paquette B: Optimization of the route of platinum drugs administration to optimize the concomitant treatment with radiotherapy for glioblastoma implanted in the Fischer rat brain. J Neurooncol. 115:365–373. 2013. View Article : Google Scholar : PubMed/NCBI

90 

da Ros M, Iorio AL, Lucchesi M, Stival A, de Martino M and Sardi I: The use of anthracyclines for therapy of CNS tumors. Anticancer Agents Med Chem. 15:721–727. 2015. View Article : Google Scholar : PubMed/NCBI

91 

Nwagwu CD, Immidisetti AV, Jiang MY, Adeagbo O, Adamson DC and Carbonell AM: Convection enhanced delivery in the setting of high-grade gliomas. Pharmaceutics. 13:5612021. View Article : Google Scholar : PubMed/NCBI

92 

Han Y and Park JH: Convection-enhanced delivery of liposomal drugs for effective treatment of glioblastoma multiforme. Drug Deliv Transl Res. 10:1876–1887. 2020. View Article : Google Scholar : PubMed/NCBI

93 

El Demerdash N, Kedda J, Ram N, Brem H and Tyler B: Novel therapeutics for brain tumors: Current practice and future prospects. Expert Opin Drug Deliv. 17:9–21. 2020. View Article : Google Scholar : PubMed/NCBI

94 

Mizuta Y, Tokuda K, Guo J, Zhang S, Narahara S, Kawano T, Murata M, Yamaura K, Hoka S, Hashizume M and Akahoshi T: Sodium thiosulfate prevents doxorubicin-induced DNA damage and apoptosis in cardiomyocytes in mice. Life Sci. 257:1180742020. View Article : Google Scholar : PubMed/NCBI

95 

Du K, Xia Q, Heng H and Feng F: Temozolomide-doxorubicin conjugate as a double intercalating agent and delivery by apoferritin for glioblastoma chemotherapy. ACS Appl Mater Interfaces. 12:34599–34609. 2020. View Article : Google Scholar : PubMed/NCBI

96 

Liu J, Zhang Y, Chen T, Chen H, He H, Jin T, Wang J and Ke Y: Environmentally self-adaptative nanocarriers suppress glioma proliferation and stemness via codelivery of shCD163 and doxorubicin. ACS Appl Mater Interfaces. 12:52354–52369. 2020. View Article : Google Scholar : PubMed/NCBI

97 

Horescu C, Elena Cioc C, Tuta C, Sevastre AS, Tache DE, Alexandru O, Artene SA, Danoiu S, Dricu A and Stefana Oana P: The effect of temozolomide in combination with doxorubicin in glioblastoma cells in vitro. J Immunoassay Immunochem. 41:1033–1043. 2020. View Article : Google Scholar : PubMed/NCBI

98 

Maksimenko O, Malinovskaya J, Shipulo E, Osipova N, Razzhivina V, Arantseva D, Yarovaya O, Mostovaya U, Khalansky A, Fedoseeva V, et al: Doxorubicin-loaded PLGA nanoparticles for the chemotherapy of glioblastoma: Towards the pharmaceutical development. Int J Pharm. 572:1187332019. View Article : Google Scholar : PubMed/NCBI

99 

Muniswamy VJ, Raval N, Gondaliya P, Tambe V, Kalia K and Tekade RK: ‘Dendrimer-Cationized-Albumin’ encrusted polymeric nanoparticle improves BBB penetration and anticancer activity of doxorubicin. Int J Pharm. 555:77–99. 2019. View Article : Google Scholar : PubMed/NCBI

100 

Li GZ, Hu YH, Li DY, Zhang Y, Guo HL, Li YM, Chen F and Xu J: Vincristine-induced peripheral neuropathy: A mini-review. Neurotoxicology. 81:161–171. 2020. View Article : Google Scholar : PubMed/NCBI

101 

Yang L, Xu X and Zheng J: Microtubule-associated protein 2 knockdown sensitizes glioma cells to vincristine treatment. Neuroreport. 31:197–204. 2020. View Article : Google Scholar : PubMed/NCBI

102 

De Witt M, Gamble A, Hanson D, Markowitz D, Powell C, Al Dimassi S, Atlas M, Boockvar J, Ruggieri R and Symons M: Repurposing mebendazole as a replacement for vincristine for the treatment of brain tumors. Mol Med. 23:50–56. 2017. View Article : Google Scholar : PubMed/NCBI

103 

Bernstock JD, Ye D, Gessler FA, Lee YJ, Peruzzotti-Jametti L, Baumgarten P, Johnson KR, Maric D, Yang W, Kögel D, et al: Topotecan is a potent inhibitor of SUMOylation in glioblastoma multiforme and alters both cellular replication and metabolic programming. Sci Rep. 7:74252017. View Article : Google Scholar : PubMed/NCBI

104 

Serwer LP, Noble CO, Michaud K, Drummond DC, Kirpotin DB, Ozawa T, Prados MD, Park JW and James CD: Investigation of intravenous delivery of nanoliposomal topotecan for activity against orthotopic glioblastoma xenografts. Neuro Oncol. 13:1288–1295. 2011. View Article : Google Scholar : PubMed/NCBI

105 

Upadhyayula PS, Spinazzi EF, Argenziano MG, Canoll P and Bruce JN: Convection enhanced delivery of topotecan for gliomas: A single-center experience. Pharmaceutics. 13:392020. View Article : Google Scholar : PubMed/NCBI

106 

Kaiser MG, Parsa AT, Fine RL, Hall JS, Chakrabarti I and Bruce JN: Tissue distribution and antitumor activity of topotecan delivered by intracerebral clysis in a rat glioma model. Neurosurgery. 47:1391–1399. 2000. View Article : Google Scholar : PubMed/NCBI

107 

Wang Y, Kong X, Guo Y, Wang R and Ma W: Continuous dose-intense temozolomide and cisplatin in recurrent glioblastoma patients. Medicine (Baltimore). 96:e62612017. View Article : Google Scholar : PubMed/NCBI

108 

Badruddoja MA, Pazzi M, Sanan A, Schroeder K, Kuzma K, Norton T, Scully T, Mahadevan D and Ahmadi MM: Phase II study of bi-weekly temozolomide plus bevacizumab for adult patients with recurrent glioblastoma. Cancer Chemother Pharmacol. 80:715–721. 2017. View Article : Google Scholar : PubMed/NCBI

109 

Herrlinger U, Tzaridis T, Mack F, Steinbach JP, Schlegel U, Sabel M, Hau P, Kortmann RD, Krex D, Grauer O, et al: Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): A randomised, open-label, phase 3 trial. Lancet. 393:678–688. 2019. View Article : Google Scholar : PubMed/NCBI

110 

Kim SH, Yoo H, Chang JH, Kim CY, Chung DS, Kim SH, Park SH, Lee YS and Yang SH: Procarbazine and CCNU chemotherapy for recurrent glioblastoma with MGMT promoter methylation. J Korean Med Sci. 33:e1672018. View Article : Google Scholar : PubMed/NCBI

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May-2022
Volume 47 Issue 5

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Spandidos Publications style
Zhou Y, Wang W, Chen N, Wang L and Huang J: Research progress of anti-glioma chemotherapeutic drugs (Review). Oncol Rep 47: 101, 2022.
APA
Zhou, Y., Wang, W., Chen, N., Wang, L., & Huang, J. (2022). Research progress of anti-glioma chemotherapeutic drugs (Review). Oncology Reports, 47, 101. https://doi.org/10.3892/or.2022.8312
MLA
Zhou, Y., Wang, W., Chen, N., Wang, L., Huang, J."Research progress of anti-glioma chemotherapeutic drugs (Review)". Oncology Reports 47.5 (2022): 101.
Chicago
Zhou, Y., Wang, W., Chen, N., Wang, L., Huang, J."Research progress of anti-glioma chemotherapeutic drugs (Review)". Oncology Reports 47, no. 5 (2022): 101. https://doi.org/10.3892/or.2022.8312