Notice of retraction: Auraptene-induced cytotoxicity mechanisms in human malignant glioblastoma (U87) cells: role of reactive oxygen species (ROS).

[This retracts the article DOI: 10.17179/excli2019-1136.].

The Potential Therapeutic Impact of Metformin in Glioblastoma Multiforme.

In terms of frequency and aggressiveness, glioblastoma multiforme (GBM) is undoubtedly the most frequent and fatal primary brain tumor. Despite advances in clinical management, the response to current treatments is dismal, with a 2-year survival rate varying between 6 and 12 percent. Metformin, a derivative of biguanide widely used in treating type 2 diabetes, has been shown to extend the lifespan of patients with various malignancies. There is limited evidence available on the long-term survival of GBM patients who have taken metformin. This research examined the literature to assess the connection between metformin's anticancer properties and GBM development. Clinical findings, together with the preclinical data from animal models and cell lines, are included in the present review. This comprehensive review covers not only the association of hyperactivation of the AMPK pathway with the anticancer activity of metformin but also other mechanisms underpinning its role in apoptosis, cell proliferation, metastasis, as well as its chemo-radio-sensitizing behavior against GBM. Current challenges and future directions for developments and applications of metformin-based therapeutics are also discussed.

Ferula gummosa gum exerts cytotoxic effects against human malignant glioblastoma multiforme in vitro.

Background and purpose: Ferula gummosa (F. gummosa), a potent medicinal herb, has been shown to possess anticancer activities in vitro. The present examination evaluated the cytotoxic and apoptogenic impacts of F. gummosa gum on the U87 glioblastoma cells. Experimental approach: MTT assay to determine the cell viability, flow cytometry by annexin V/FITC-PI to apoptosis evaluation, reactive oxygen species (ROS) assay, and quantitative RT-PCR were performed. Findings / Results: The results revealed that F. gummosa inhibited the growth of U87 cells in a concentration- and time-dependent manner with IC50 values of 115, 82, and 52 µg/mL obtained for 24, 48, and 72 h post-treatment, respectively. It was also identified that ROS levels significantly decreased following 4, 12, and 24 h after treatment. The outcomes of flow cytometry analysis suggested that F. gummosa induced a sub-G1 peak which translated to apoptosis in a concentration-dependent manner. Further examination revealed that F. gummosa upregulated Bax/Bcl-2 ratio and p53 genes at mRNA levels. Conclusion and implications: Collectively, these findings indicate that sub-G1 apoptosis and its related genes may participate in the cytotoxicity of F. gummosa gum in U87 cells.

Recent advances in glioblastoma multiforme therapy: A focus on autophagy regulation.

Despite conventional treatment options including chemoradiation, patients with the most aggressive primary brain tumor, glioblastoma multiforme (GBM), experience an average survival time of less than 15 months. Regarding the malignant nature of GBM, extensive research and discovery of novel treatments are urgently required to improve the patients' prognosis. Autophagy, a crucial physiological pathway for the degradation and recycling of cell components, is one of the exciting targets of GBM studies. Interventions aimed at autophagy activation or inhibition have been explored as potential GBM therapeutics. This review, which delves into therapeutic techniques to block or activate autophagy in preclinical and clinical research, aims to expand our understanding of available therapies battling GBM.

Anticancer Mechanisms of Berberine: A Good Choice for Glioblastoma Multiforme Therapy.

The most typical malignant brain tumor, glioblastoma multiforme (GBM), seems to have a grim outcome, despite the intensive multi-modality interventions. Literature suggests that biologically active phytomolecules may exert anticancer properties by regulating several signaling pathways. Berberine, an isoquinoline alkaloid, has various pharmacological applications to combat severe diseases like cancer. Mechanistically, it inhibits cell proliferation and invasion, suppresses tumor angiogenesis, and induces cell apoptosis. The antitumoral effect of berberine in GBM is increasingly recognized. This review sheds new light on the regulatory signaling mechanisms of berberine in various cancers, proposing its potential role as a therapeutic agent for GBM.

Nanoparticle-based drug delivery systems in cancer: A focus on inflammatory pathways.

It has become necessary to accept the clinical reality of therapeutic agents targeting the cancer-associated immune system. In recent decades, several investigations have highlighted the role of inflammation in cancer development. It has now been recognized that inflammatory cells secrete mediators, including enzymes, chemokines, and cytokines. These secreted substances produce an inflammatory microenvironment that is critically involved in cancer growth. Inflammation may enhance genomic instability leading to DNA damage, activation of oncogenes, or compromised tumor suppressor activity, all of which may promote various phases of carcinogenesis. Conventional cancer treatment includes surgery, radiation, and chemotherapy. However, treatment failure occurs because current strategies are unable to achieve complete local control due to metastasis. Nanoparticles (NPs) are a broad spectrum of drug carriers typically below the size of 100 nm, targeting tumor sites while reducing off-target consequences. More importantly, NPs can stimulate innate and adaptive immune systems in the tumor microenvironment (TME); hence, they induce a cancer-fighting immune response. Strikingly, targeting cancer cells with NPs helps eliminate drug resistance and tumor recurrence, as well as prevents inflammation. Throughout this review, we provide recent data on the role of inflammation in cancer and explore nano-therapeutic initiatives to target significant mediators, for example, nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukins (ILs) associated with cancer-related inflammation, to escort the immunomodulators to cancer cells and associated systemic compartments. We also highlight the necessity of better identifying inflammatory pathways in cancer pathophysiology to develop effective treatment plans.

Advantages and drawbacks of dexamethasone in glioblastoma multiforme.

The most widespread, malignant, and deadliest type of glial tumor is glioblastoma multiforme (GBM). Despite radiation, chemotherapy, and radical surgery, the median survival of afflicted individuals is about 12 months. Unfortunately, existing therapeutic interventions are abysmal. Dexamethasone (Dex), a synthetic glucocorticoid, has been used for many years to treat brain edema and inflammation caused by GBM. Several investigations have recently shown that Dex also exerts antitumoral effects against GBM. On the other hand, more recent disputed findings have questioned the long-held dogma of Dex treatment for GBM. Unfortunately, steroids are associated with various undesirable side effects, including severe immunosuppression and metabolic changes like hyperglycemia, which may impair the survival of GBM patients. Current ideas and concerns about Dex's effects on GBM cerebral edema, cell proliferation, migration, and its clinical outcomes were investigated in this study.

How do phosphodiesterase-5 inhibitors affect cancer? A focus on glioblastoma multiforme.

Since the discovery of phosphodiesterase-5 (PDE5) enzyme overexpression in the central nervous system (CNS) malignancies, investigations have explored the potential capacity of current PDE5 inhibitor drugs for repositioning in the treatment of brain tumors, notably glioblastoma multiforme (GBM). It has now been recognized that these drugs increase brain tumors permeability and enhance standard chemotherapeutics effectiveness. More importantly, studies have highlighted the promising antitumor functions of PDE5 inhibitors, e.g., triggering apoptosis, suppressing tumor cell growth and invasion, and reversing tumor microenvironment (TME) immunosuppression in the brain. However, contradictory reports have suggested a pro-oncogenic role for neuronal cyclic guanosine monophosphate (cGMP), indicating the beneficial function of PDE5 in the brain of GBM patients. Unfortunately, due to the inconsistent preclinical findings, only a few clinical trials are evaluating the therapeutic value of PDE5 inhibitors in GBM treatment. Accordingly, additional studies should be conducted to shed light on the precise effect of PDE5 inhibitors in GBM biology regarding the existing molecular heterogeneities among individuals. Here, we highlighted and discussed the previously investigated mechanisms underlying the impacts of PDE5 inhibitors in cancers, focusing on GBM to provide an overview of current knowledge necessary for future studies.

Zerumbone, a ginger sesquiterpene, inhibits migration, invasion, and metastatic behavior of human malignant glioblastoma multiforme in vitro.

The most widespread and challenging aggressive malignant tumor in the brain is glioblastoma multiforme (GBM). GBM is characterized, in particular, by significant intratumor cell variability, high growth rates, and widespread invasiveness within the surrounding normal brain parenchyma. The present study aimed to examine the impact of the natural product Zerumbone, a promising sesquiterpenoid phytochemical from Zingiber zerumbet, on U-87 MG GBM cells and its underlying molecular mechanisms. At sub-lethal doses, Zerumbone exerted a concentration- and time-dependent suppression of cell migration ability utilizing scratch wound closure assay; it also inhibited GBM cells' invasion using Transwell invasion assay in a concentration-dependent fashion. The enzymatic activity of matrix metalloproteinase (MMP)-2/-9 and their protein expression has also been reduced by administration of Zerumbone. Furthermore, Zerumbone was revealed to downregulate the mRNA expression level of IL-1ß and MCP-1, two genes contributing to MMPs expression. We also found that Zerumbone exerted an inhibitory effect on the expression of Akt and total p44/42 MAPK (Erk1/Erk2) against U-87 MG cells. These findings collectively provide further proof for the possible molecular signaling basis of the antimetastatic effects of Zerumbone as a promising phytochemical, indicating a therapeutic strategy for the treatment of GBM through repression of migration, invasion, and metastasis.

Targeting the PD-1/PD-L1 pathway in glioblastoma multiforme: Preclinical evidence and clinical interventions.

Glioblastoma multiforme (GBM), as one of the immunosuppressive and common intrinsic brain tumors in adults, remains an intractable malignancy to manage. Since the standard of care for treatment, which includes surgery and chemoradiation, has not provided a sustainable and durable response in affected patients, seeking novel therapeutic approaches to treat GBM seems imperative. Immunotherapy, a breakthrough for cancer treatment, has become an attractive tool for combating cancer with the potential to access the blood-brain-barrier (BBB). In this regard, programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), as major immunological checkpoints, have drawn considerable interest due to their effectiveness in a spectrum of highly-aggressive neoplasms through negative regulation of the T-cell-mediated immune response. Nevertheless, due to the immunosuppressive microenvironment of GBM, the efficacy of these immune checkpoint inhibitors (ICIs), when used as monotherapy, has been unfavorable and lacks sufficient beneficial outcomes for GBM patients. A variety of clinical studies are attempting to evaluate the combination of ICIs (neoadjuvant/adjuvant) and existing treatment guidelines to strengthen their effectiveness; however, the exact mechanism of this signaling axis affects the consequences of immune therapy remains elusive. This review provides an overview of the PD-1/PD-L1 pathway, currently approved ICIs for clinical use, preclinical and clinical trials of PD-1/PD-L1 as monotherapy, and when used concomitantly with other GBM treatments.

Neurokinin-1 Receptor (NK-1R) Antagonists: Potential Targets in the Treatment of Glioblastoma Multiforme.

The current standard of care in glioblastoma multiforme (GBM), as the most morbid brain tumor, is not adequate, despite substantial progress in cancer therapy. Among patients receiving current standard treatments, including surgery, irradiation, and chemotherapy, the overall survival (OS) period with GBM is less than one year. The high mortality frequency of GBM is due to its aggressive nature, including accelerated growth, deregulated apoptosis, and invasion into surrounding tissues. The understanding of the molecular pathogenesis of GBM is, therefore, crucial for identifying, designing, and repurposing potential agents in future therapeutic approaches. In recent decades, it has been apparent that several neurotransmitters, specifically substance P (SP), an undecapeptide in the family of neuropeptides tachykinins, are found in astrocytes. After binding to the neurokinin-1 receptor (NK-1R), the SP controls cancer cell growth, exerts antiapoptotic impacts, stimulates cell invasion/metastasis, and activates vascularization. Since SP/NK-1R signaling pathway is a growth driver in many cancers, this potential mechanism is proposed as an additional target for treating GBM. Following an evaluation of the function of both SP and its NK-1R inhibitors in neoplastic cells, we recommend a unique and promising approach for the treatment of patients with GBM.

Effects of statins on mitochondrial pathways.

Statins are a family of drugs that are used for treating hyperlipidaemia with a recognized capacity to prevent cardiovascular disease events. They inhibit ß-hydroxy ß-methylglutaryl-coenzyme A reductase, i.e. the rate-limiting enzyme in mevalonate pathway, reduce endogenous cholesterol synthesis, and increase low-density lipoprotein clearance by promoting low-density lipoprotein receptor expression mainly in the hepatocytes. Statins have pleiotropic effects including stabilization of atherosclerotic plaques, immunomodulation, anti-inflammatory properties, improvement of endothelial function, antioxidant, and anti-thrombotic action. Despite all beneficial effects, statins may elicit adverse reactions such as myopathy. Studies have shown that mitochondria play an important role in statin-induced myopathies. In this review, we aim to report the mechanisms of action of statins on mitochondrial function. Results have shown that statins have several effects on mitochondria including reduction of coenzyme Q10 level, inhibition of respiratory chain complexes, induction of mitochondrial apoptosis, dysregulation of Ca2+ metabolism, and carnitine palmitoyltransferase-2 expression. The use of statins has been associated with the onset of additional pathological conditions like diabetes and dementia as a result of interference with mitochondrial pathways by various mechanisms, such as reduction in mitochondrial oxidative phosphorylation, increase in oxidative stress, decrease in uncoupling protein 3 concentration, and interference in amyloid-ß metabolism. Overall, data reported in this review suggest that statins may have major effects on mitochondrial function, and some of their adverse effects might be mediated through mitochondrial pathways.

Effects of Rhus coriaria L. hydroalcoholic extract on the lipid and antioxidant profile in high fat diet-induced hepatic steatosis in rats.

Oxidative stress is related to increased fat deposition in the liver, known as hepatic steatosis. The present study is an evaluation of the anti-oxidative and antihyperlipidemic effects of the hydroalcoholic extract of Rhus coriaria L. (HARE) in rats on a high-fat diet (HFD). Twenty male Wistar rats were divided into four groups: control, HFD, HFD + HARE 50 mg/kg/day, and HFD + HARE 250 mg/kg/day for 12 weeks. Animals were weighed weekly and treated with the HARE extract for 12 weeks by gavage. Subsequently, the histopathological changes, oxidative markers, and lipid profile were evaluated. Statistical analysis was performed using the one-way analysis of variance (ANOVA) for multiple comparisons. First, the active ingredients of the extract were determined by HPLC. Then, the levels in the serum lipid profile (TG, cholesterol, HDL, and LDL) in rats fed with the HFD + HARE were analyzed where a significant reduction was observed. The HFD proved to increase the activity of the liver enzymes, the serum lipid levels, and the malondialdehyde (MDA) level. The ferric-reducing antioxidant activity power (FRAP), catalase (CAT), and superoxide dismutase (SOD) catalytic activity were reduced in the liver homogenate of HFD rats compared to the controls. Additionally, the aforementioned liver enzymes activities were reduced in response to HARE. Evaluation of oxidative stress determined a reduction in the MDA level while a raised FRAP was confirmed. In accordance with the present results, histopathological observations have also demonstrated that HARE ameliorated grade-1 hepatic steatosis induced by HFD. Taken together, the findings of this study introduce HARE as a future potential therapeutic agent in treating hepatic steatosis and reducing oxidative damages of an HFD in the liver.

Protective Role of Natural Products in Glioblastoma Multiforme: A Focus on Nitric Oxide Pathway.

In spite of therapeutic modalities such as surgical resection, chemotherapy, and radiotherapy, Glioblastoma Multiforme (GBM) remains an incurable fatal disease. This necessitates further therapeutic options that could enhance the efficacy of existing modalities. Nitric Oxide (NO), a short-lived small molecule, has been revealed to play a crucial role in the pathophysiology of GBM. Several studies have demonstrated that NO is involved in apoptosis, metastasis, cellular proliferation, angiogenesis, invasion, and many other processes implicated in GBM pathobiology. Herein, we elaborate on the role of NO as a therapeutic target in GBM and discuss some natural products affecting the NO signaling pathway.

Effects of statins on brain tumors: a review.

Evidence from preclinical studies suggests that the competitive HMG-CoA reductase (HMGCR) inhibitors universally known as 'statins,' in addition to being powerful drugs that reduce cholesterol and improve cardiovascular risk, also have promising antitumor properties. Statins appear to enhance the treatment outcome of various cancers before and concurrent with other cancer treatment interventions. Glioblastoma multiforme (GBM), a particularly invasive cerebral tumor associated with high mortality, holds a poor median overall survival (OS) of around one year after surgical resection followed by concurrent radiation and chemotherapy. Recently, statins have increasingly appeared as potential adjuvant drugs for the treatment of GBM because of their potential to suppress cell growth, survival, migration, metastasis, inflammation, angiogenesis, and promote apoptosis during both in vitro and in vivo studies. However, the clinical outcomes of statins on the survival of patients with GBM are still controversial. This study aims to review and address some of the documented effects of statin drugs when focusing entirely on cancer treatment, especially GBM, including concurrent statin therapy with chemotherapeutic agents.

Anti-tumor Effects of Curcuminoids in Glioblastoma Multiforme: An Updated Literature Review.

Glioblastoma Multiforme (GBM) is a poorly curable brain tumor because of its extremely invasive nature. Curcuminoids, as potential phytochemicals extracted from Curcuma Longa L., have been documented for their chemopreventive and antitumor activities against several types of malignancies. These compounds exert these effects via modulation of multiple signaling pathways and molecular targets at different stages of tumor progression, proliferation, and metastasis. In experimental studies, curcuminoids have demonstrated promising therapeutic benefits to overcome GBM. Curcuminoids have been shown to exert their anti-GBM effects through regulation of angiogenesis, apoptosis, autophagy, metastasis, invasion, as well as potential molecular targets, including receptor tyrosine kinases, Sonic Hedgehog, and NF-κB. This study reviews the observations regarding the impact of curcumin and its derivatives on GBM and the potential of translating the research findings into the clinic.

Minocycline in Treating Glioblastoma Multiforme: Far beyond a Conventional Antibiotic.

One of the most lethal forms of CNS pathologies is glioblastoma multiforme (GBM) that represents high invasiveness, uncontrolled proliferation, and angiogenic features. Its invasiveness is responsible for the high recurrence even after maximal surgical interventions. Minocycline is a semisynthetic analog of tetracyclines with potential anti-inflammatory and anticancer effects, distinct from its antimicrobial activity. In this review, we highlight the importance and the cytotoxic mechanisms of minocycline on GBM pathophysiology. Considering the role of certain enzymes in autophagy, apoptosis, tumor cell invasion, and metastatic ability, the possible use of tetracyclines for cancer therapy should be investigated, especially GBM. The present study is, therefore, going to cover the main topics in minocycline pharmacology to date, encouraging its consideration as a new treatment approach for cancer and GBM.

Potential protective roles of phytochemicals on glutamate-induced neurotoxicity: A review.

Glutamate, as an essential neurotransmitter, has been thought to have different roles in the central nervous system (CNS), including nerve regeneration, synaptogenesis, and neurogenesis. Excessive glutamate causes an up-regulation of the multiple signaling pathways, including phosphoinositide-3 kinase/protein kinase B (PI3K/Akt), Akt/mammalian target of rapamycin (mTOR) protein, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)1/2, and autophagy that are involved in neurodegenerative diseases pathophysiology. There are numerous findings on curcumin, astaxanthin, thymoquinone, and berberine, as natural products, which have outstanding effects in cell signaling far beyond their anti-oxidant activity, considering as a potential therapeutic target for glutamate excitotoxicity. Herein, we address the role of glutamate as a potential target in neurodegenerative diseases and discuss the protective effects of certain phytochemicals on glutamate-induced neurotoxicity.

Modulation of Calcium Signaling in Glioblastoma Multiforme: A Therapeutic Promise for Natural Products.

Glioblastoma multiforme (GBM) continues as one of the most lethal cerebral cancers despite standard therapeutic modalities, such as maximum surgical resection and chemoradiation. The minimal effectiveness of existing therapies necessitates the development of additional drug candidates that could improve the prognosis of GBM patients. Accumulating evidence suggests that calcium (Ca2+) is involved in the processes of cell proliferation, metastasis, angiogenesis, migration, and invasiveness. Therefore, Ca2+ could serve as a crucial regulator of tumorigenesis and a potential treatment target in GBM. In this context, specific natural products are known to modulate Ca2+ signaling pathways implicated in tumor growth, apoptosis, angiogenesis, and development of GBM. Here, the focus is on the function of Ca2+ as a therapeutic target in GBM and reviewing certain natural products that affect the signaling pathways of Ca2+.

The Current State of Potential Therapeutic Modalities for Glioblastoma Multiforme: A Clinical Review.

Glioblastoma multiforme (GBM), as the most lethal brain tumor, continues to be incurable. Considering the high mortality rate of GBM, it is crucial to develop new treatment approaches. Conventional therapies, including maximal surgical resection, radiation therapy, and chemotherapy (typically temozolomide), have not led to significant changes in the survival rates of GBM patients. However, emerging modalities, such as the use of tyrosine kinase inhibitors, mTOR inhibitors, NF-κB modulators, nitrosoureas, and immunotherapeutic agents have shown promising in improving GBM outcomes. In this context, we reviewed the current status of GBM treatment, the efficacy of existing standard therapies in improving disease outcomes, and future therapeutic directions.