|Year : 2019 | Volume
| Issue : 4 | Page : 159-164
Repurposing drugs for the treatment of glioma
Chengming Xu, Yaodong Zhao, Congyan Wu, Lei Li
Department of Neurosurgery, Shanghai General Hospital of Nanjing Medical University, Shanghai, China
|Date of Submission||12-Dec-2019|
|Date of Acceptance||31-Dec-2019|
|Date of Web Publication||23-Jan-2020|
Dr. Yaodong Zhao
100 Haining Road, Hongkou District, Shanghai
Source of Support: None, Conflict of Interest: None
Glioma is the most common primary tumor of the central nervous system. In addition to traditional anticancer drugs, some common nonchemotherapeutic drugs have been considered by some scholars, such as nonsteroidal anti-inflammatory drugs, metformin, and statins. These drugs are often used for the treatment of noncancerous diseases. However, it was found that those drugs could be considered for the clinical treatment of glioma, especially in combination with chemotherapy drugs, which may improve the treatment effect. This process is called “repurposing.” Here, we aim to review these drugs and the literature. These “old drugs” have been used clinically for many years, and their safety and feasibility are high. Such combinations are expected to become a new strategy in chemotherapy for glioma in the clinic.
Keywords: Aldehyde dehydrogenase inhibitors, cyclooxygenase-2, deacetylase inhibitors, glioma, ion channels, metformin, repurposing drugs, statins
|How to cite this article:|
Xu C, Zhao Y, Wu C, Li L. Repurposing drugs for the treatment of glioma. Glioma 2019;2:159-64
| Introduction|| |
Glioma is the most common primary tumor of the central nervous system. Although treatment for glioma has improved in recent years, survival has not improved. In addition to traditional anticancer drugs, some common nonchemotherapeutic drugs have been considered by some scholars, such as metformin and statins., These nonchemotherapeutic drugs are often used for the treatment of noncancerous diseases, and they have been used safely in the clinic for many years., Their toxicology and pharmacokinetics are relatively well known. This process is called “repurposing.” It was found that some of the drugs could be considered for the clinical treatment of glioma, especially in combination with chemotherapy drugs, which may improve the treatment effect. Here, we aim to review relevant literature, find out these drugs, and identify their mechanisms of action, which might be helpful to researchers and clinicians to explore the combination strategy for glioma.
| Database Search Strategy|| |
The articles on drugs in this review were retrieved by relevant keywords. English language, Chinese language, and full-text articles published in and before 2019 were included in this review. We searched databases such as PubMed to identify relevant publications. The literature search strategy was conducted as follows: six keywords: (1) Cyclooxygenase-2, (2) Drugs targeting ion channels, (3) Aldehyde dehydrogenase inhibitors, (4) Adenosine monophosphate-activated protein kinase pathway activators, (5) Deacetylase inhibitors, and (6) Statins were combined with glioma. Six queries were obtained. We screened the reference list of the included studies to identify other potentially useful studies. First, the titles and abstracts and then the full texts for keywords to find those that were potentially suitable were screened. The data extraction process focused on the information about the effects of each drug on tumors and gliomas. According to the important information provided in the literature, the literature search can be conducted again to obtain additional information.
| Cyclooxygenase-2|| |
Nonsteroidal anti-inflammatory drugs are used to treat acute and chronic pain by inhibiting the action of cyclooxygenase (COX). Celecoxib, aspirin, and other nonsteroidal anti-inflammatory drugs are common and are used often in rheumatoid arthritis, osteoarthritis, and other diseases. Such drugs mainly relieve pain and inflammation through the COX-2/prostaglandin E2 (PGE2) pathway. Interestingly, this pathway can also be targeted as an antitumor strategy. The high expression of COX-2 in glioma is closely related to its proliferation, apoptosis, angiogenesis, metastasis, and immunodeficiency. PGE2 is the main metabolite of COX-2.
Tumor immune escape is a major factor in the development of glioma. When there are few tumor cells, it is not easy to illicit an immune response; however, when an immune response begins to develop, immune-suppressive factors are secreted into the microenvironment of glioma. Factors such as PGE2, transforming growth factor-β, and interleukin-10 may suppress the immune response, leading to tumor cell immune escape. COX-2 can inhibit the activity of macrophages, natural killer cells, and T cells and inhibit the production of cytokines such as interferon-y and interleukin-10 through its catalytic product, PGE2, which can increase the level of intracellular cyclic adenosine monophosphate. Interleukin-10 can reduce the surface molecule expression of dendritic cells and inhibit the differentiation, maturation, and antigen-presenting abilities of dendritic cells such that they cannot activate T cells to recognize and kill tumor cells, which leads to tumor immune escape.
In mouse glioma models, it was found that the tumor volume of the celecoxib treatment group was significantly smaller than that of the control group, and the expression of COX-2, vascular endothelial growth factor, and transforming growth factor-β protein in the tissue was decreased. It has been experimentally confirmed that celecoxib treatment increases the sensitivity of malignant tumors to radiotherapy and chemotherapy, but the combination has not been translated into the clinic, and research is still in its infancy.
| Drugs Targeting Ion Channels (Potassium Channels and Calcium Channels)|| |
In clinical treatment, potassium channel blockers such as amiodarone and sotalol are often used to treat arrhythmias. They block voltage-sensitive potassium channels, reduce potassium ion flux, and prolong the action potential duration and refractory period., Calcium channel-targeting drugs, such as verapamil, inhibit extracellular calcium influx, lead to decreased myocardial contractility, reduce heart rate, relax vasculature, reduce blood pressure, etc., for the treatment of angina and arrhythmia.
In the process of glioma development, potassium channels and calcium channels play different roles. They can participate in the proliferation, differentiation, migration, and apoptosis of tumor cells through different pathways. They are also involved in the tumor cell cycle. Potassium channels act in the mitotic cycle of cells, mainly in the following aspects: mitosis increases the expression and activity of potassium channels; potassium channel activators stimulate cell mitosis; and blockers inhibit cell mitosis. Similarly, the progression of the tumor cycle often depends on the intracellular basal concentration of Ca2+. Ru et al. analyzed calcium influx by voltage-gated potassium channels and found that it regulates the proliferation of U87 cells.
In order for metabolic activities of tumor cells to be carried out efficiently, they independently regulate the intracellular pH to form a weakly alkaline cytoplasmic environment, which is achieved by channels for molecules such as potassium ions. Therefore, inhibition of ion channel activity can lower pH, increase endonuclease activity, cause DNA fragmentation between nucleosomes, limit the activation of proto-oncogenes, and enhance the susceptibility of tumor cells to various physical and chemical factors and chemotherapy drugs, thus increasing apoptosis.
During the migration phase, glioma cells need to change their size and shape to effectively pass through the extracellular space, which is helpful for invading the barriers of normal cells. When potassium ions flow out of the cell, the cell volume becomes smaller and cells migrate easily. Glioma cells have an energy-dependent membrane protein, P-170, which is a calcium channel. When a common chemotherapeutic drug enters the extracellular fluid and passively enters the tumor cell, depending on the concentration gradient, it will be pumped out by the P-170 protein, leading to a significant decrease in the effect of chemotherapy and drug resistance. Nicardipine is a calcium ion antagonist that can be combined with P-170 to reduce drug efflux, increase intracellular drug concentration, and enhance drug effects.
Common potassium channel drugs include sulfonylureas, such as glibenclamide, and antiarrhythmic drugs such as amiodarone; calcium channel drugs include dihydropyridines such as nicardipine and phenylalkylamines such as verapamil. These drugs have been shown to be effective in regulating ion channels and can play a role in certain antitumor processes.,, Moreover, nicardipine, when used in combination with chemotherapeutic drugs, can inhibit the high expression of adenosine triphosphate-binding cassette G2, which is one mechanism by which tumors become resistant to chemotherapy. It was shown that treating a mouse glioma model with carmustine and verapamil led to tumor sizes that were significantly smaller than those seen with carmustine treatment alone. Lou and Zhao found that nimustine combined with nicardipine was effective in the treatment of advanced glioma.
| Aldehyde Dehydrogenase Inhibitors|| |
Aldehyde dehydrogenase (ALDH) is mainly involved in the oxidative metabolism of aldehydes in cells. Disulfiram is an ALDH1 inhibitor. ALDH catalyzes the transformation of intracellular 9-cis-retinene into an important signaling molecule in the cell, retinoic acid. Retinoic acid can regulate a variety of biological processes in cells, including tumor cell proliferation, differentiation, and apoptosis and cell cycle arrest. Moreover, ALDH is also involved in the epithelial–mesenchymal transition process of tumor cells. Through this process, tumor cells can escape the lysis of T-cells, and this escape is closely related to the spread, recurrence, and progression of malignant tumors.
In glioma stem cells, ALDH can promote the transformation of tumor stem cells from a neuronal pretype to an interstitial type, which significantly increases the malignant degree of the glioma. ALDH can also increase the chemoresistance of cancer stem cells. After the chemotherapeutic drug enters the cell, its aldehyde group can be oxidized to the corresponding carboxylic acid, and the corresponding toxic substance is converted into a nontoxic form. It can be seen that cancer stem cells with more ALDH are often more tolerant to chemotherapy than cells with less ALDH. Therefore, the use of antitumor drugs after treatment with ALDH inhibitors can achieve superior results. These findings show that the application of ALDH inhibitors is important for combating tumors and delaying recurrence. Adam et al. found that the colony-forming ability of ALDH1A1-positive glioma cells was significantly stronger than that of ALDH1A1-negative cells; in addition, the expression of ALDH1A1 is closely related to the Ki67 proliferation index, and the prognosis of patients with high expression is often poor. Lun et al. found that disulfiram can be used to inhibit doxorubicin being pumped out of cells, leading to an increased concentration of doxorubicin in tumor cells and effectively enhancing the anticancer effect of doxorubicin. Rae et al. studied malignant glioma cells and found that disulfiram could enhance the growth inhibition of tumor cells by radiation.
| Adenosine Monophosphate-Activated Protein Kinase Pathway Activators|| |
A large number of clinical studies have found that the commonly used drug metformin can reduce the incidence of tumors in diabetic patients,, and some studies have suggested that metformin has a small inhibitory effect on the growth of a variety of malignant diseases, such as glioma, breast cancer, and gastric cancer.,, Metformin can induce apoptosis in gliomas by activating the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway.
AMPK is a protein kinase in cells, which is a receptor related to cellular energy. When AMPK is activated, it may inhibit the growth of tumor cells through two pathways, namely decreasing intracellular cyclin D1 via the p53/p21 pathway and blocking the cell cycle in the G1 phase. Mammalian target of rapamycin is one of the target proteins of AMPK, and activated AMPK can inhibit the activity of the target protein to promote apoptosis. When mammalian target of rapamycin activity is weakened, the downstream target molecules ribosomal protein S6 kinase and eukaryotic promoter 4E binding protein are dephosphorylated to reduce intracellular protein synthesis and cell growth.,
Studies have shown that metformin can reverse the increase in Akt activity caused by temozolomide and that metformin can inhibit the mammalian target of rapamycin and its downstream signaling pathway, which is the main mechanism by which temozolomide and metformin synergistically clear germline stem cells.,, Experimental studies suggest that the combination of temozolomide and metformin has a higher inhibition rate in treating glioma and more synergistic effects on glioma stem cells than monotherapy., Maraka's team found that metformin is feasible and safe to use in combination with temozolomide for the treatment of glioblastoma by studying its use as an antiglioma agent.
| Deacetylase Inhibitors|| |
In recent years, it has been found that sodium valproate can bind to the catalytic center of deacetylases and inhibit deacetylase and cellular kinase activity, thereby affecting histone acetylation, transcription, and DNA methylation to regulate gene transcription. The mitogen- AMPK signaling pathway ultimately inhibits glioma angiogenesis and induces the differentiation and apoptosis of different tumor cells. Some studies have shown that sodium valproate (deacetylase inhibitor) can decrease the viability of glioma stem cells, reduce the formation of glioma stem cells, and lead to the apoptosis of glioma stem cells.,
At the same time, deacetylase inhibitors can also exert antitumor effects via multiple pathways, such as decreased invasiveness and migration of glioma cells and increased apoptosis of glioma cells, by inhibiting signal transduction and phosphorylation of activators. Deacetylase inhibitors can also inhibit the activity of nuclear transcription factor-κB and induce the apoptosis of U266 cells by inhibiting the phosphorylation of the inhibitor of nuclear transcription factor-κB. Studies have shown that high expression of cyclin D1 in glioma cells can lead to uncontrolled cell proliferation, and cyclin D1 can also bind to histone deacetylase to promote its own transcription.,, After treatment with deacetylase inhibitors, the expression of cyclin D1 protein in glioma stem cells decreased, and the cell cycle was blocked in the G1 phase. The possible causes include the downregulation of the expression of cyclin D1 resulting in glioma stem cells being unable to enter S phase and the decrease in cyclin D1 gene expression induced via the inhibition of cyclin D1 and histone deacetylase binding.
Deacetylase inhibitors, such as sodium valproate, are commonly used in the prevention and treatment of epilepsy. However, they can stop the cell cycle, promote cell differentiation, induce apoptosis, and inhibit tumor cell migration and angiogenesis of tumor tissue, making deacetylase inhibitors possible candidates for antitumor adjuvant therapy. After treatment of glioma stem cells with different concentrations of sodium valproate, the colony formation rate of glioma stem cells decreased significantly with increasing concentration, and the inhibitory effect was concentration dependent. Sodium valproate can be used alone or in combination with the traditional chemotherapy drug temozolomide to treat gliomas with extremely high malignancy. It has been reported that valproate–temozolomide synergistically inhibits the proliferation and migration of temozolomide-sensitive glioma cell lines (T98 and U138) and induces apoptosis and autophagy. Combination therapy can reduce the growth of tumors in glioma transplant models. In addition, Phase II clinical trials have shown that combination treatments with valproate, radiotherapy, and temozolomide when compared to monotherapies are better tolerated by drug-sensitive glioma patients; they prolong patient survival time and improve their quality of life.
| Statins|| |
Statins are common lipid-lowering drugs. They can inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which can effectively reduce cholesterol levels and reduce the risk of cardiovascular disease. HMG-CoA reductase is the rate-limiting enzyme of the mevalonate pathway, and statins can affect the mevalonate pathway. The mevalonate pathway is controlled by the p53 gene, which activates the expression of the ABCA1 gene. The ABCA1 protein blocks the maturation of the sterol regulatory element-binding protein 2 protein, thereby inhibiting the mevalonate pathway. The efficacy of various statins depends mainly on their affinity for HMG-CoA reductase. They competitively inhibit the activity of HMG-CoA reductase and prevent downstream product formation to affect cell signaling and apoptosis.,
Damage to cellular DNA causes p53 to be activated and expressed and acts on the downstream p21 protein, which serves as a cyclin-dependent protein kinase inhibitor and binds to the cyclin–cyclin dependent kinase complex to inhibit the corresponding protein kinase activity. Phosphorylated retinoblastoma proteins accumulate, preventing the E2F transcription factor from being activated and causing G1 phase arrest. Studies have shown that statins regulate the activity of extracellular protein kinases and p38 proteins by regulating external signals and transmit signals to cells through the mitogen-AMPK signaling pathway, inducing the expression of related cytokines to inhibit cell growth., By regulating the mevalonate pathway, as HMG-CoA reductase inhibitors, statins cause tumor cell cycle arrest and apoptosis, thereby preventing the growth of tumors, such as gliomas. For example, some studies have found that rosuvastatin can be used to treat glioma stem cells., Different concentrations of lovastatin have different inhibitory effects on glioma stem cells in a concentration-dependent manner and can reduce the expression of Bcl-2 gene.
| Conclusion|| |
These “old drugs” have been used clinically for many years, and their safety and feasibility are high. When using traditional antitumor drugs, possible combinations with these “old drugs” might enhance the therapeutic effect. Such combinations are expected to become a new strategy in chemotherapy for glioma in the clinic.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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