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MTS assay showing the viability of U-87 and U-251 cells after 48 and 72 h of treatment with various concentrations of (A) 2-DG (0.5–20 mM) and (B) WP1122 (0.25–5 mM). CHX (20 μM) was used as a positive control. Significant differences between the treatment means and control value are indicated by ** p < 0.01 and *** p < 0.001.
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Over the last decade, we have seen tremendous progress in research on 2-deoxy-D-glucose (2-DG) and its analogs. Clinical trials of 2-DG have demonstrated the challenges of using 2-DG as a monotherapy, due to its poor drug-like characteristics, leading researchers to focus on improving its bioavailability to tissue and organs. Novel 2-DG analogs suc...
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Citations
... CNS penetrant drugs, while scarce, have been developed, such as the 2-DG mimetic dichloroacetate (96). The 2-DG prodrug WP1122 has direct cytotoxic effects on glioblastoma cell survival when combined with histone deacetylase inhibitors (97). Dichloroacetate is being evaluated in an ongoing phase II clinical trial of patients with glioblastoma (NCT05120284) (91). ...
Immunometabolism is a burgeoning field of research that investigates how immune cells harness nutrients to drive their growth and functions. Myeloid cells play a pivotal role in tumor biology, yet their metabolic influence on tumor growth and antitumor immune responses remains inadequately understood. This Review explores the metabolic landscape of tumor-associated macrophages, including the immunoregulatory roles of glucose, fatty acids, glutamine, and arginine, alongside the tools used to perturb their metabolism to promote antitumor immunity. The confounding role of metabolic inhibitors on our interpretation of myeloid metabolic phenotypes will also be discussed. A binary metabolic schema is currently used to describe macrophage immunological phenotypes, characterizing inflammatory M1 phenotypes, as supported by glycolysis, and immunosuppressive M2 phenotypes, as supported by oxidative phosphorylation. However, this classification likely underestimates the variety of states in vivo. Understanding these nuances will be critical when developing interventional metabolic strategies. Future research should focus on refining drug specificity and targeted delivery methods to maximize therapeutic efficacy.
... 2-DG is an analog of glucose and is transported across the BBB by the glucose carrier system, mainly glucose transporter 1 (GLUT1) [8]. 2-Deoxy-D-glucose (2-DG) is a well-known glycolysis inhibitor with confirmed cytotoxic action in various cancer models, including GBM [9]. GBM cells are susceptible to 2-DG action, since glycolysis is the main pathway of glucose utilization and ATP synthesis [10]. ...
... The obtained results indicate that U-87 and U-251 GBM cells characterize the highly glycolytic phenotype even in normoxia conditions. Our observations are in agreement with the well-known fact that GBM, along with pancreatic cancer, represents the most glycolytic tumors [9]. According to the MTS viability assay, selected WP1234 treatments (100 and 500 µM) significantly reduced U-87 cell viability compared to normoxic conditions ( Figure 5, left panel). ...
... The obtained results indicate that U-87 and U-251 GBM cells characterize the highly glycolytic phenotype even in normoxia conditions. Our observations are in agreement with the well-known fact that GBM, along with pancreatic cancer, represents the most glycolytic tumors [9]. It is postulated that the limited oxygen concentration and hypoxia make GBM cells almost utterly dependent on glycolysis-mediated glucose utilization. ...
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis. Despite significant progress in drug development, the blood–brain barrier (BBB) continues to limit the use of novel chemotherapeutics. Thus, our attention has been focused on the design, synthesis, and testing of small-molecule anticancer agents that are able to penetrate the BBB. One such compound is the D-glucose analog, 2-deoxy-D-glucose (2-DG), which inhibits glycolysis and induces GBM cell death. 2-DG has already been tested in clinical trials but was not approved as a drug, in part due to inadequate pharmacokinetics. To improve the pharmacokinetic properties of 2-DG, a series of novel derivatives was synthesized. Herein, we report the biological effects of WP1234, a 2-ethylbutyric acid 3,6-diester of 2-DG that can potentially release 2-ethylbutyrate and 2-DG inside the cells when metabolized. Using biochemical assays and examining cell viability, proliferation, protein synthesis, and apoptosis induction, we assessed the cytotoxic potential of WP1234. WP1234 significantly reduced the viability of GBM cells in a dose- and time-dependent manner. The lactate and ATP synthesis assays confirmed the inhibition of glycolysis elicited by released 2-DG. Furthermore, an evaluation of histone deacetylases (HDAC) activity revealed that the 2-ethylbutyrate action resulted in HDAC inhibition. Overall, these results demonstrated that WP1234 is a bifunctional molecule with promising anticancer potential. Further experiments in animal models and toxicology studies are needed to evaluate the efficacy and safety of this new 2-DG derivative.
... Combined treatment might be of great interest in order to develop effective therapeutic protocols for glioblastoma [7][8][9][10][11][12]. In this respect, we have recently reported a possible combined therapeutic approach for GBM based on the use of microRNA inhibitors and anti-GBM molecules. ...
... It should be underlined that combined treatments appear of great interest in the development of anticancer approaches [7][8][9][10][11][12], since they are expected to obtain the same biological or therapeutic effect using lower concentrations of two or more drugs, thereby limiting side effects [58]. Importantly, combined therapy might be of great importance in the management of Glioblastoma (GBM), a lethal malignant tumor needing novel therapeutic options. ...
(1) Background: In the development of new and more effective anticancer approaches, combined treatments appear of great interest. Combination therapy could be of importance in the management of glioblastoma (GBM), a lethal malignancy that accounts for 42% of cancer of the central nervous system, with a median survival of 15 months. This study aimed to verify the activity on a glioblastoma cancer cell line of one of the most active compounds of a novel series of tubulin polymerization inhibitors based on the 1-(3′,4′,5′-trimethoxyphenyl)-2-aryl-1H-imidazole scaffold, used in combination with a miRNA inhibitor molecule targeting the oncomiRNA miR-10b-5p. This microRNA was selected in consideration of the role of miR-10b-5p on the onset and progression of glioblastoma. (2) Methods: Apoptosis was analyzed by Annexin-V and Caspase 3/7 assays, efficacy of the anti-miR-10b-5p was assessed by determining the miR-10b-5p content by RT-qPCR. (3) Results: The results obtained show that a “combination therapy” performed by combining the use of an anti-miR-10b-5p and a 1-(3′,4′,5′-trimethoxyphenyl)-2-aryl-1H-imidazole derivative is an encouraging strategy to boost the efficacy of anticancer therapies and at the same time to reduce side effects.
... We recently described that novel 2-DG analogs could also be promising candidates for anti-GBM drugs [34]. Especially, the diacetylated 2-DG derivative-WP1122-can potently induce GBM cell death in U-87 and U-251 GBM cells [55]. The cytotoxic effect of WP1122 was synergistically potentiated with concomitant inhibition of histone deacetylases (HDAC) by sodium butyrate (NaBt) or sodium valproic (NaVPA) [55]. ...
... Especially, the diacetylated 2-DG derivative-WP1122-can potently induce GBM cell death in U-87 and U-251 GBM cells [55]. The cytotoxic effect of WP1122 was synergistically potentiated with concomitant inhibition of histone deacetylases (HDAC) by sodium butyrate (NaBt) or sodium valproic (NaVPA) [55]. In December 2021, Moleculin Biotech received an FDA allowance to begin a phase 1 study of WP1122 to treat GBM [56]. ...
... Additionally, our recent preclinical studies support the hypothesis about the beneficial effects of HDACi as synergistic agents for anti-GBM treatment. Using the acetylated 2-DG analog-WP1122combined with HDACi (sodium butyrate, NaBt, and sodium valproate, NaVPA), we obtained a strong cytotoxic effect against GBM cells [55]. Thus, the combination of previously described glycolysis inhibitors (DCA and AEO) in more advanced stages of their clinical development with Vorinostat could be an attractive therapeutic option for GBM treatment. ...
Glioblastoma multiforme (GBM) is the deadliest and the most heterogeneous brain cancer. The median survival time of GBM patients is approximately 8 to 15 months after initial diagnosis. GBM development is determined by numerous signaling pathways and is considered one of the most challenging and complicated-to-treat cancer types. Standard GBM therapy consist of surgery followed by radiotherapy or chemotherapy, and combined treatment. Current standard of care (SOC) does not offer a significant chance for GBM patients to combat cancer, and the selection of available drugs is limited. For almost 20 years, there has been only one drug, Temozolomide (TMZ), approved as a first-line GBM treatment. Due to the limited efficacy of TMZ and the high rate of resistant patients, the implementation of new chemotherapeutics is highly desired. However, due to the unique properties of GBM, many challenges still need to be overcome before reaching a ‘breakthrough’. This review article describes the most recent compounds introduced into clinical trials as drug candidates for GBM chemotherapy.
Glucose metabolism is a crucial biological pathway maintaining the activation of extra- and intracellular signaling pathways involved in the immune response. Immune cell stimulation via various environmental factors results in their activation and metabolic reprogramming to aerobic glycolysis. Different immune cells exhibit cell-type-specific metabolic patterns when performing their biological functions. Numerous published studies have shed more light on the importance of metabolic reprogramming in the immune system. Moreover, this knowledge is crucial for revealing new ways to target inflammatory pathologic states, such as autoimmunity and hyperinflammation. Here, we discuss the role of glycolysis in immune cell activity in physiological and pathological conditions, and the potential use of inhibitors of glycolysis for disease treatment.
In the combat of treating cancer recent therapeutic approaches are focused towards enzymatic targets as they occupy a pivotal participation in the cascade of oncogenesis and malignancy. There are several enzymes that modulate the epigenetic pathways and chromatin structure related to cancer mutation. Among several epigenetic mechanisms such as methylation, phosphorylation, and sumoylation, acetylation status of histones is crucial and is governed by counteracting enzymes like histone acetyl transferase (HAT) and histone deacetylases (HDAC) which have contradictory effects on the histone acetylation. HDAC inhibition induces chromatin relaxation which forms euchromatin and thereby initiates the expression of certain transcription factors attributed with apoptosis, which are mostly correlated with the expression of the p21 gene and acetylation of H3 and H4 histones. Most of the synthetic and natural HDAC inhibitors elicit antineoplastic effect through activation of various apoptotic pathways and promoting cell cycle arrest at various phases. Due to their promising chemo preventive action and low cytotoxicity against normal host cells, bioactive substances like flavonoids, alkaloids, and polyphenolic compounds from plants have recently gained importance. Even though all bioactive compounds mentioned have an HDAC inhibitory action, some of them have a direct effect and others enhance the effects of the standard well known HDAC inhibitors. In this review, the action of plant derived compounds against histone deacetylases in a variety of in vitro cancer cell lines and in vivo animal models are articulated.
Seizures are among the most common clinical signs in people with glioblastoma. Advances over the past 5 years, including new clinical trial data, have increased the understanding of why some individuals with glioblastoma are susceptible to seizures, how seizures manifest clinically, and what implications seizures have for patient management. The pathophysiology of epilepsy in people with glioblastoma relates to a combination of intrinsic epileptogenicity of tumour tissue, alterations in the tumour and peritumoural microenvironment, and the physical and functional disturbance of adjacent brain structures. Successful management of epilepsy in people with glioblastoma remains challenging; factors such as drug-drug interactions between cancer therapies and antiseizure medications, and medication side-effects, can affect seizure outcomes and quality of life. Advances in novel therapies provide some promise for people with glioblastoma; however, the effects of these therapies on seizures are yet to be fully determined. Looking forward, insights into electrical activity as a driver of tumour cell growth and the intrinsic hyperexcitability of tumour tissue might represent useful targets for treatment and disease modification. There is a pressing need for large randomised clinical trials in this field.
Cervical cancer is one of the most common female malignant tumors, with typical cancer metabolism characteristics of increased glycolysis flux and lactate accumulation. 2‐Deoxy‐D‐glucose (2‐DG) is a glycolysis inhibitor that acts on hexokinase, the first rate‐limiting enzyme in the glycolysis pathway. In this research, we demonstrated that 2‐DG effectively reduced glycolysis and impaired mitochondrial function in cervical cancer cell lines HeLa and SiHa. Cell function experiments revealed that 2‐DG significantly inhibited cell growth, migration, and invasion, and induced G0/G1 phase arrest at non‐cytotoxic concentrations. In addition, we found that 2‐DG down‐regulated Wingless‐type (Wnt)/β‐catenin signaling. Mechanistically, 2‐DG accelerated the degradation of β‐catenin protein, which resulted in the decrease of β‐catenin expression in both nucleus and cytoplasm. The Wnt agonist lithium chloride and β‐catenin overexpression vector could partially reverse the inhibition of malignant phenotype by 2‐DG. These data suggested that 2‐DG exerted its anti‐cancer effects on cervical cancer by co‐targeting glycolysis and Wnt/β‐catenin signaling. As expected, the combination of 2‐DG and Wnt inhibitor synergistically inhibited cell growth. It is noteworthy that, down‐regulation of Wnt/β‐catenin signaling also inhibited glycolysis, indicating a similar positive feedback regulation between glycolysis and Wnt/β‐catenin signaling. In conclusion, we investigated the molecular mechanism by which 2‐DG inhibits the progression of cervical cancer in vitro, elucidated the interregulation between glycolysis and Wnt/β‐catenin signaling, and preliminarily explored the effect of combined targeting of glycolysis and Wnt/β‐catenin signaling on cell proliferation, which provides more possibilities for the formulation of subsequent clinical treatment strategies.
Despite recent advances in multimodality therapy for glioblastoma (GB) incorporating surgery, radiotherapy, chemotherapy and targeted therapy, the overall prognosis remains poor. One of the interesting targets for GB therapy is the histone deacetylase family (HDAC). Due to their pleiotropic effects on, e.g., DNA repair, cell proliferation, differentiation, apoptosis and cell cycle, HDAC inhibitors have gained a lot of attention in the last decade as anti-cancer agents. Despite their known underlying mechanism, their therapeutic activity is not well-defined. In this review, an extensive overview is given of the current status of HDAC inhibitors for GB therapy, followed by an overview of current HDAC-targeting radiopharmaceuticals. Imaging HDAC expression or activity could provide key insights regarding the role of HDAC enzymes in gliomagenesis, thus identifying patients likely to benefit from HDACi-targeted therapy.
