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Emerging therapeutic strategies in glioblastsoma: drug repurposing, mechanisms of resistance, precision medicine, and technological innovations.

Glioblastoma (GBM) is an aggressive Grade IV brain tumor with a poor prognosis. It results from genetic mutations, epigenetic changes, and factors within the tumor microenvironment (TME). Traditional treatments like surgery, radiotherapy, and chemotherapy provide limited survival benefits due to the tumor's heterogeneity and resistance mechanisms. This review examines novel approaches for treating GBM, focusing on repurposing existing medications such as antipsychotics, antidepressants, and statins for their potential anti-GBM effects. Advances in molecular profiling, including next-generation

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… Disulfiram Disulfiram, originally used to treat alcoholism, shows promise as a repurposed therapy for GBM [ 123 ]. It inhibits ALDH, leading to acetaldehyde buildup and alcohol intolerance. … Given its safety profile and BBB penetration, disulfiram is a promising candidate for GBM and potentially pediatric brain tumor treatment, though further research is required. …

Cancer Metabolism as a Therapeutic Target and Review of Interventions.

Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost. The Warburg hypothesis states that cancer cells have an altered cell metabolism towards anaerobic glycolysis. Given this metabolic reprogramming in cancer cells, it is possible to target cancers metabolically by depriving them of glucose. In addition to dietary and lifestyle modifications which work on tumors metabolically, there are a panoply of nutritional supplements and repurposed drugs associated with cancer prevention and

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… Disulfiram Disulfiram (DSF) inhibits aldehyde dehydrogenase, leading to acetaldehyde accumulation and unpleasant effects when alcohol is consumed, making it an anti-alcoholism drug; however, it has been repurposed as a potent cancer treatment, showing anti-tumor effects in preclinical studies and recent … PubChem Disulfiram Available online: https://pubchem.ncbi.nlm.nih.gov/compound/disulfiram (accessed on 7 September 2023) 128. Huang J. Campian J.L. Gujar A.D. Tran D.D. Lockhart A.C. DeWees T.A. Tsien C.I. Kim A.H. …

High prevalence of Behçet's disease in southern Italy.

UNLABELLED: Lopinavir is a novel protease inhibitor (PI) developed from ritonavir. Coadministration with low-dose ritonavir significantly im … navir contains 42.4% ethanol (v/v) and should not be coadministered with drugs capable of producing disulfiram-like reactions (e.g. disulfiram, metronidazole). Coadministration with saquinavir or indinavir requires no dosage adjustment, whereas coadministration with amprenavir, nevirapine or efavirenz requires a dosage increase of the coformulation typically …

Identification of a novel cuproptosis-related gene signature for multiple myeloma diagnosis.

BackgroundMultiple myeloma (MM) ranks second among the most prevalent hematological malignancies. Recent studies have unearthed the promise of cuproptosis as a novel therapeutic intervention for cancer. However, no research has unveiled the particular roles of cuproptosis-related genes (CRGs) in the prediction of MM diagnosis.MethodsMicroarray data and clinical characteristics of MM patients were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed gene analysis, least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature e

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… Disulfiram/copper markedly induced myeloma cell apoptosis through activation of JNK and intrinsic and extrinsic apoptosis pathways. Biomed Pharmacother. 2020;126:110048. 10.1016/j.biopha.2020.110048 20. Jin N, Zhu X, Cheng F, Zhang L. … Disulfiram/copper targets stem cell‐like ALDH population of multiple myeloma by inhibition of ALDH1A1 and hedgehog pathway. JCB. 2018;119(8):6882‐6893. 10.1002/jcb.26885 21. Zhu Y, He J, Li Z, Yang W. …

Drug Repurposing of New Treatments for Neuroendocrine Tumors.

Drug repurposing or drug repositioning is the process of identifying new therapeutic uses for approved or investigational drugs beyond the original treatment indication. The discovery of new drugs for cancer therapy needs this cost-effective and time-saving alternative strategy to traditional drug development for a rapid clinical translation in Phase II/III studies, especially for unmet medical needs and rare diseases. Neuroendocrine tumors (NETs) are a heterogeneous group of rare neoplasms arising from cells of the neuroendocrine system that, though often indolent, can be aggressive and metas

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… Disulfiram, traditionally used to treat chronic alcoholism, has recently gained attention for its potential anticancer properties. … Additionally, dopastatin (used to reduce hormone production, especially in tumors), disulfiram (used for chronic alcoholism), and NSAIDs such as celecoxib might be effective treatment options for PitNETs. …

Different Strategies to Overcome Resistance to Proteasome Inhibitors-A Summary 20 Years after Their Introduction.

Proteasome inhibitors (PIs), bortezomib, carfilzomib, and ixazomib, are the first-line treatment for multiple myeloma (MM). They inhibit cytosolic protein degradation in cells, which leads to the accumulation of misfolded and malfunctioned proteins in the cytosol and endoplasmic reticulum, resulting in cell death. Despite being a breakthrough in MM therapy, malignant cells develop resistance to PIs via different mechanisms. Understanding these mechanisms drives research toward new anticancer agents to overcome PI resistance. In this review, we summarize the mechanism of action of PIs and how M

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… Disulfiram, an anti-alcoholism drug, acts as a copper and zinc chelator, thus interfering with SOD activity [ 96 ]. It appears that disulfiram can also overcome BTZ resistance both in acute myeloid leukemia and MM cell lines [ 97 , 98 ]. … Disulfiram: Mechanisms, Applications, and Challenges Antibiotics 2023 12 524 10.3390/antibiotics12030524 36978391 PMC10044060 97. Salem K. McCormick M.L. Wendlandt E. Zhan F. Goel A. …

Targetable pathways for drug repurposing in gastric cancer.

Gastric cancer (GC) is both the fifth most common cancer worldwide and the fifth in mortality. Owing to a lack of symptoms in the early stages and unspecific clinical presentation in the later stages, GC is usually diagnosed at advanced stages. This means that only approximately 60% of patients are eligible for curative treatment, and overall, GC patients have a 5-year survival rate of only 28.3%, underscoring the importance of developing new treatment strategies. Drug repurposing involves identifying new therapeutic uses for approved drugs and is a promising strategy for cancer treatment beca

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… Disulfiram is a drug that is used to treat alcohol abuse through the inhibition of acetaldehyde dehydrogenase. Disulfiram has been shown to have anticancer effects and to reverse drug resistance, inhibit DNA methylation, and induce apoptosis. … Disulfiram is catalyzed into diethyldithiocarbamate, which chelates into complexes that contain cupric ion. …

Neutrophils unveiled in chronic lymphocytic leukemia.

This review explores neutrophils' roles in chronic lymphocytic leukemia (CLL), highlighting their functions within the immune system. While neutrophils are known for fighting infections, their altered behavior in CLL significantly impacts disease progression. This review notes the reduced phagocytic abilities of neutrophils and the increased formation of neutrophil extracellular traps (NETs) in patients with CLL. It also examines the effects of CLL treatments, including chemotherapy, immunotherapy and targeted therapies, on neutrophils' count and function, stressing the need for improved strat

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… Disulfiram Disulfiram, a medication approved by the U.S. Food and Drug Administration for alcohol use disorder, inhibits aldehyde dehydrogenase. Studies have demonstrated its ability to block gasdermin D (GSDMD) in macrophages. … Disulfiram inhibits neutrophil extracellular trap formation and protects rodents from acute lung injury and SARS-CoV-2 infection. JCI Insight. (2022) 7:e157342. doi: 10.1172/jci.insight.157342, PMID: 159. Ohms M, Moller S, Laskay T. …

Unlocking hidden potential: advancements, approaches, and obstacles in repurposing drugs for cancer therapy.

High rates of failure, exorbitant costs, and the sluggish pace of new drug discovery and development have led to a growing interest in repurposing "old" drugs to treat both common and rare diseases, particularly cancer. Cancer, a complex and heterogeneous disease, often necessitates a combination of different treatment modalities to achieve optimal outcomes. The intrinsic polygenicity of cancer, intricate biological signalling networks, and feedback loops make the inhibition of a single target frequently insufficient for achieving the desired therapeutic impact. As a result, addressing these c

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… Azar K Kannappan V Liu Y Butcher K Morris M Armesilla A Disulfiram targets glioblastoma-stem-like cells in vitro and in vivo Neuro Oncol 2018 20 i20 10.1093/neuonc/nox238.089 84. … Lu C Li X Ren Y Zhang X Disulfiram: a novel repurposed drug for cancer therapy Cancer Chemother Pharm 2021 87 159 72 10.1007/s00280-020-04216-8 33426580 141. …

NF-κB in Cell Deaths, Therapeutic Resistance and Nanotherapy of Tumors: Recent Advances.

The transcription factor nuclear factor-κB (NF-κB) plays a complicated role in multiple tumors. Mounting evidence demonstrates that NF-κB activation supports tumorigenesis and development by enhancing cell proliferation, invasion, and metastasis, preventing cell death, facilitating angiogenesis, regulating tumor immune microenvironment and metabolism, and inducing therapeutic resistance. Notably, NF-κB functions as a double-edged sword exerting positive or negative influences on cancers. In this review, we summarize and discuss recent research on the regulation of NF-κB in cancer cell deaths,

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… Disulfiram is a well-known anti-alcohol drug and has anti-cancer activity by eliminating cancer stem cells (CSCs) and reversing chemoresistance. The cytotoxicity of disulfiram relies on copper and the disulfiram-copper complex could prevent NF-κB activation [ 165 ]. … Disulfiram, a Clinically Used Anti-Alcoholism Drug and Copper-Binding Agent, Induces Apoptotic Cell Death in Breast Cancer Cultures and Xenografts via Inhibition of the Proteasome Activity Cancer Res. 2006 66 10425 10433 10.1158/0008-5472.CAN-06-2126 17079463 …

Drug Repurposing in Oncology: A Systematic Review of Randomized Controlled Clinical Trials.

Quality pharmacological treatment can improve survival in many types of cancer. Drug repurposing offers advantages in comparison with traditional drug development procedures, reducing time and risk. This systematic review identified the most recent randomized controlled clinical trials that focus on drug repurposing in oncology. We found that only a few clinical trials were placebo-controlled or standard-of-care-alone-controlled. Metformin has been studied for potential use in various types of cancer, including prostate, lung, and pancreatic cancer. Other studies assessed the possible use of t

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… Drugs under investigation include meclofenamate, sodium valproate, propranolol, etodolac, atorvastatin, and disulfiram. Table 2 Characteristics of included studies that presented results in the systematic review. … Disulfiram repurposing combined with nutritional copper supplement as add-on to chemotherapy in recurrent glioblastoma (DIRECT): Study protocol for a randomized controlled trial F1000Research 2018 7 1797 10.12688/f1000research.16786.1 30647912 PMC6325620 47. Aman J. Duijvelaar E. Botros L. …

Drug repurposing in KRAS G12C-mutant NSCLC: a focus on resistance mechanisms and clinical strategies.

KRAS G12C-mutant non-small cell lung cancer (NSCLC) has transitioned from a therapeutically problematic disease to a precision-targetable cancer, anchored by the landmark approvals of sotorasib and adagrasib. Yet despite these advances, responses remain limited in duration and multiple mechanisms of rapid adaptive resistance emerge under inhibitor pressure. These resistance mechanisms define a therapeutic vulnerability map that can be addressed by repurposing approved agents with established safety profiles. This review emphasises the current understanding of KRAS G12C biology, integrates upda

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… glycolysis (TP-medium) | Grade B (translational evidence) (Viveiros et al. 2019 ; Arrieta et al. 2019 ) Auranofin | Rheumatoid arthritis | Oxidative stress/ROS management | Proposed modulation of oxidative stress pathways (TP-low) | Grade C (exploratory preclinical ROS-targeting) (Doumat et al. 2023 ) Disulfiram … Disulfiram (proteasome inhibitor) An anti-alcoholism drug, disulfiram, inhibits the proteasome and NF-κB signalling while activating apoptotic pathways selectively in cancer cells. A phase 2/3 trial ( NCT00312819 ) evaluated disulfiram + chemotherapy in metastatic NSCLC (Nechushtan et al. 2015 ). …

What Drives Innovation: The Canadian Touch on Liposomal Therapeutics.

Liposomes are considered one of the most successful drug delivery systems (DDS) given their established utility and success in the clinic. In the past 40⁻50 years, Canadian scientists have made ground-breaking discoveries, many of which were successfully translated to the clinic, leading to the formation of biotech companies, the creation of research tools, such as the Lipex Extruder and the NanoAssemblr™, as well as contributing significantly to the development of pharmaceutical products, such as Abelcet®, MyoCet®, Marqibo®, Vyxeos®, and Onpattro™, which are making positive impacts on patient

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… Initial studies by Wehbe et al. explored formulation strategies for diethyldithiocarbamate (DDC), a metabolite generated after disulfiram is administered. Disulfiram is an anti-alcoholic agent known to inhibit aldehyde dehydrogenase [ 78 ]. … The clinical use of disulfiram (Antabuse ® ): A review J. Psychoact. Drugs 1988 20 243 261 10.1080/02791072.1988.10472495 3069984 79. San Andres M.P. Marina M.L. Vera S. …

Bioabsorbable polymers in cancer therapy: latest developments.

Cancer is a devastating disease, being responsible for 13 % of all deaths worldwide. One of the main challenges in treating cancer concerns the fact that anti-cancer drugs are not highly specific for the cancer cells and the "death" of healthy cells in the course of chemotherapy treatment is inevitable. In this sense, the use of drug delivery systems (DDS) can be seen as a powerful tool to minimize or overcome this very important issue. DDS can be designed to target specific tissues in order to mitigate side effects. Bioabsorbable polymers, due to their inherent characteristics, and because th

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… The millirods were processed by two different techniques, viz., hot melt extrusion (HME) and injection moulding (IM), and loaded with disulfiram (DSF). … McConville C Tawari P Wang W Hot melt extruded and injection moulded disulfiram-loaded PLGA millirods for the treatment of glioblastoma multiforme via stereotactic injection Int J Pharm. 2015 494 73 82 10.1016/j.ijpharm.2015.07.072 26235918 121. …

Диметилфумарат уменьшает травму от печени ишемии и реперуляции путем подавления сигнала CGAS-STING.

Повреждение печени во время периоперационной фазы операции на печени часто происходит в результате печени. Неправильная активация сигнала СТИНГ может вызвать чрезмерную воспламенение реакции на усугубление печени. Диметилфумарат (DMF) — разрешенный УЛХ иммунодулятор, используемый для лечения множественного склероза и псориаза в силу его заметных свойств против воспаления. Однако механизм и целевые показатели ДМФ в области иммуномодуляции остаются неясными. Здесь мы обнаружили, что DMF подавляет активацию CGAS-STING, индуцируемую HSV-1, ДНК яичек и митохондриальная ДНК в различных клетках. DMF

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… succinating GSDMD and GAPDH. 27 , 28 , 29 Additionally, cGAS‐STING signaling has crosstalk with NRF2 activation, pyroptosis, and glycolysis. 30 , 31 To assess if DMF impacts on cGAS‐STING signaling relies on these three pathways, we treated THP‐1 cells with ML385 (NRF2 inhibitor), disulfiram … Antibodies and reagents The chemical reagents were used as follows: poly(I:C) from InvivoGen, HT‐DNA from Sigma, 2′3'‐cGAMP from APExBIO, diABZI from Selleck, DMF, MMF, ML385, disulfiram and heptelidic acid from MedChemExpress, and DMS from RHAWN. …

Redefining Breast Cancer Care by Harnessing Computational Drug Repositioning.

Breast cancer faces significant therapeutic challenges, particularly for triple-negative breast cancer (TNBC), due to limited targeted therapies and drug resistance. Drug repositioning leverages existing safety and pharmacokinetic data to expedite the identification of new indications with cost-effective benefits compared to de novo drug discovery. In this critical narrative review, we examine recent advances in computational repositioning strategies for breast cancer, focusing on network-based methods, computer-aided drug design, artificial intelligence and machine learning, transcriptomic si

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… Danish health records showed a decrease in mortality among users of disulfiram for several types of cancer, including breast cancer. These real-world data findings, derived from retrospective EHR-style data, spurred interest in repositioning disulfiram [ 88 ]. … For example, a phase II clinical trial ( NCT03323346 ) is currently unfolding to evaluate the efficacy of disulfiram combined with copper in patients with metastatic breast cancer, aiming to establish clinical evidence for introducing this combination as a therapeutic option for patients who have exhausted …

Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-Angiotensin System.

Patients with glioblastoma (GB), a highly aggressive brain tumor, have a median survival of 14.6 months following neurosurgical resection and adjuvant chemoradiotherapy. Quiescent GB cancer stem cells (CSCs) invariably cause local recurrence. These GB CSCs can be identified by embryonic stem cell markers, express components of the renin-angiotensin system (RAS) and are associated with circulating CSCs. Despite the presence of circulating CSCs, GB patients rarely develop distant metastasis outside the central nervous system. This paper reviews the current literature on GB growth inhibition in r

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… The study combines the use of aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritanvir, and sertraline, in conjunction with temozolomide. The initial results indicated little toxicity, maintenance of good quality of life, and hints of effectiveness. … CUSP9* treatment protocol for recurrent glioblastoma: Aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide. Oncotarget. 2014;5:8052–8082. doi: 10.18632/oncotarget.2408. 96. …

Drug-induced oxidative stress in cancer treatments: Angel or devil?

Oxidative stress (OS), defined as redox imbalance in favor of oxidant burden, is one of the most significant biological events in cancer progression. Cancer cells generally represent a higher oxidant level, which suggests a dual therapeutic strategy by regulating redox status (i.e., pro-oxidant therapy and/or antioxidant therapy). Indeed, pro-oxidant therapy exhibits a great anti-cancer capability, attributing to a higher oxidant accumulation within cancer cells, whereas antioxidant therapy to restore redox homeostasis has been claimed to fail in several clinical practices. Targeting the redox

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… Disulfiram, also known as antabuse, was discovered almost a century ago as an agent that inhibits acetaldehyde dehydrogenase, resulting in an immediate hangover when alcohol is ingested. … In addition to its use in alcoholism treatment, disulfiram has been found to shift the ratio of GSH: oxidized glutathione (GSSG) to the oxidized state and induce OS. …

Research progress on ferroptosis in Myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a group of malignancies characterized by clonal proliferation of hematopoietic stem cells, ineffective hematopoiesis, peripheral cytopenias, and a high risk of transformation to acute myeloid leukemia. Current therapeutic strategies for MDS have limited efficacy. Thus, identifying new therapeutic targets and prognostic biomarkers is a critical future research direction. Ferroptosis, a new type of iron-dependent programmed cell death, has become a recent hotspot in the field of oncology research. Recent results have demonstrated that iron metabolism, lipid me

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… Ferroptosis induction combined with cuproptosis Cuproptosis is a novel form of cell death induced by various copper ion carrier drugs such as Elesclomol, Disulfiram, and NSC319726 ( Tang D. et al., 2024 ). … Disulfiram/copper shows potent cytotoxic effects on myelodysplastic syndromes via inducing Bip-mediated apoptosis and suppressing autophagy . Eur. J. Pharmacol. 902 , 174107 . 10.1016/j.ejphar.2021.174107 33865831 Zhang L. Xu Y. Cheng Z. Zhao J. Wang M. Sun Y. ( 2024a ). …

Control of viral infections by epigenetic-targeted therapy.

Epigenetics is defined as the science that studies the modifications of gene expression that are not owed to mutations or changes in the genetic sequence. Recently, strong evidences are pinpointing toward a solid interplay between such epigenetic alterations and the outcome of human cytomegalovirus (HCMV) infection. Guided by the previous possibly promising experimental trials of human immunodeficiency virus (HIV) epigenetic reprogramming, the latter is paving the road toward two major approaches to control viral gene expression or latency. Reactivating HCMV from the latent phase ("shock and k

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… ( NCT03198559 ) with vorinostat, as disulfiram was shown to reactivate latent HIV-1 in a primary CD4+ T cell model [ 199 ]. … Disulfiram reactivates latent HIV-1 in a Bcl-2-transduced primary CD4+ T cell model without inducing global T cell activation. J Virol. 2011;85:6060–6064. doi: 10.1128/JVI.02033-10. 200. Yeo W, Chung HC, Chan SL, Wang LZ, Lim R, Picus J, et al. …