Drug repositioning: Using psychotropic drugs for the treatment of glioma

You, Fangting; Zhang, Caiyi; Liu, Xiaoxiao; Ji, Daofei; Zhang, Tong; Yu, Rutong; Gao, Shangfeng

doi:10.1016/j.canlet.2021.12.014

Cited by 22 publications

(11 citation statements)

References 85 publications

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“…An ongoing search exploits the possibility of repurposing antipsychotics for the treatment of medical conditions other than psychiatric diseases, such as cancer [ 515 , 516 , 517 ]. These studies could shed light on new non-canonical MOA of antipsychotics that may be crucial also in the development of novel druggable targets in schizophrenia.…”

Section: Resultsmentioning

confidence: 99%

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

Bartolomeis¹,

Ciccarelli²,

Simone³

et al. 2023

IJMS

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Schizophrenia is a severe psychiatric illness affecting almost 25 million people worldwide and is conceptualized as a disorder of synaptic plasticity and brain connectivity. Antipsychotics are the primary pharmacological treatment after more than sixty years after their introduction in therapy. Two findings hold true for all presently available antipsychotics. First, all antipsychotics occupy the dopamine D2 receptor (D2R) as an antagonist or partial agonist, even if with different affinity; second, D2R occupancy is the necessary and probably the sufficient mechanism for antipsychotic effect despite the complexity of antipsychotics’ receptor profile. D2R occupancy is followed by coincident or divergent intracellular mechanisms, implying the contribution of cAMP regulation, β-arrestin recruitment, and phospholipase A activation, to quote some of the mechanisms considered canonical. However, in recent years, novel mechanisms related to dopamine function beyond or together with D2R occupancy have emerged. Among these potentially non-canonical mechanisms, the role of Na2+ channels at the dopamine at the presynaptic site, dopamine transporter (DAT) involvement as the main regulator of dopamine concentration at synaptic clefts, and the putative role of antipsychotics as chaperones for intracellular D2R sequestration, should be included. These mechanisms expand the fundamental role of dopamine in schizophrenia therapy and may have relevance to considering putatively new strategies for treatment-resistant schizophrenia (TRS), an extremely severe condition epidemiologically relevant and affecting almost 30% of schizophrenia patients. Here, we performed a critical evaluation of the role of antipsychotics in synaptic plasticity, focusing on their canonical and non-canonical mechanisms of action relevant to the treatment of schizophrenia and their subsequent implication for the pathophysiology and potential therapy of TRS.

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Section: Resultsmentioning

confidence: 99%

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

Bartolomeis¹,

Ciccarelli²,

Simone³

et al. 2023

IJMS

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“…One of the major, yet often surprisingly overlooked, obstacles in developing drugs to treat neurological and psychiatric conditions, including dementia, is that "more than 98% of small molecule drugs and almost 100% of large molecule drugs are precluded from drug delivery to brain" [100,101]. A major feature of the tricyclic compounds that have been approved to treat psychiatric conditions such as psychosis and depression is that in general and almost by definition these compounds cross the blood-brain barrier after oral administration [102]. We therefore assessed if compound GM310 would be concentrated in the brain after i.p.…”

Section: Results Initial Screen For Compounds Which Delay Abeta Prote...mentioning

confidence: 99%

Novel small molecules inhibit proteotoxicity and inflammation: Mechanistic and therapeutic implications for Alzheimer’s Disease, healthspan and lifespan- Aging as a consequence of glycolysis

Mobbs

Litke

Roh

et al. 2023

Preprint

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Alzheimers Disease (AD) and other age-related diseases are increasingly among the most devastating strains on public health systems as the population ages, yet few treatments produce clinically significant protection. Although it is widely agreed that proteotoxicity drives impairments in AD and other neurological diseases, many preclinical and case-report studies indicate that increased microglial production of pro-inflammatory cytokines such as TNF-a also drive AD and other neurological conditions. The critical importance of inflammation, especially TNF-a, in driving age-related diseases is indicated by the fact that Humira, simply a monoclonal antibody to TNF-a, has become the top-selling drug in history, even though it does not cross the blood-brain barrier. Since target-based strategies to discover drugs to treat these diseases have largely failed, we developed parallel high-throughput phenotypic screens to discover small molecules which inhibit age-related proteotoxicity in a C. elegans model of AD, AND microglia inflammation (LPS-induced TNF-a). In the initial screen of 2560 compounds to delay Abeta proteotoxicity in C. elegans, the most protective compounds were, in order, phenylbutyrate (HDAC inhibitor), methicillin (beta lactam antibiotic), and quetiapine (tricyclic antipsychotic). These classes of compounds are already robustly implicated as potentially protective in AD and other neurodegenerative diseases. In addition to quetiapine, several other tricyclic antipsychotic drugs also delayed age-related Abeta proteotoxicity and microglial TNF-a. Based on these results we carried out extensive structure-activity relationship studies, leading to the synthesis of a novel congener of quetiapine, #310, which inhibits a wide range of pro-inflammatory cytokines in mouse and human myeloid cells, and delays impairments in animal models of AD, Huntingtons, and stroke. #310 is highly concentrated in brain after oral delivery with no apparent toxicity, increases lifespan, and produces molecular responses highly similar to those produced by dietary restriction. Among these molecular responses are induction of CBP and inhibition of CtBP and CSPR1, and inhibition of glycolysis, reversing gene expression profiles and elevated glycolysis associated with AD. Several lines of investigation strongly supported that the protective effects of #310 are mediated by activating the Sigma-1 receptor, whose protective mechanisms in turn also entail inhibiting glycolysis. Reduced glycolysis has also been implicated in the generally protective effects of dietary restriction, rapamycin, reduced IFG-1 activity, and ketones during aging, suggesting that aging is driven at least in part by glycolysis. Consistent with these observations, the glycolytic inhibitor 2-DG inhibited microglial TNF-a and other markers of inflammation, delayed Abeta proteotoxicity, and increased lifespan. To our knowledge no other known molecule exhibits all these protective effects which makes #310 an attractive candidate to treat AD and other age-related diseases. Indeed it is plausible that #310 or possibly even more effective congeners could displace Humira as a widely used therapy for age-related diseases. Furthermore, these studies suggest that the efficacy of tricyclic compounds to treat psychosis and depression could be due to their anti-inflammatory effects mediated by the Sigma-1 receptor, rather than the D2 receptor, and that better drugs to treat these conditions with fewer metabolic side effects could be developed by focusing on the Sigma-1 receptor rather than the D2 receptor. These results strongly support the value of phenotypic screens to discover drugs to treat AD and other age-related diseases and to elucidate mechanisms driving those diseases.

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“…We have also explored the sensitivity of common chemotherapy drugs in different risk groups; this can provide valuable information for personalized treatment of patients. Notably, the potential of psychotropic drugs in the treatment of gliomas has emerged in recent years with the further development of drug repositioning, which may lead to new breakthroughs in the treatment of gliomas [ 43 , 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

Basement-Membrane-Related Gene Signature Predicts Prognosis in WHO Grade II/III Gliomas

Zhang

Lai

Sun

2022

Genes

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Gliomas that are classified as grade II or grade III lesions by the World Health Organization (WHO) are highly aggressive, and some may develop into glioblastomas within a short period, thus portending the conferral of a poor prognosis for patients. Previous studies have implicated basement membrane (BM)-related genes in glioma development. In this study, we constructed a prognostic model for WHO grade II/III gliomas in accordance with the risk scores of BM-related genes. Differentially expressed genes (DEGs) in the glioma samples relative to normal samples were screened from the GEO database, and five prognostically relevant BM-related genes, including NELL2, UNC5A, TNC, CSPG4, and SMOC1, were selected using Cox regression analyses for the risk score model. The median risk score was calculated, based on which high- and low-risk groups of patients were generated. The clinical information, pathological information, and risk group were combined to establish a prognostic nomogram. Both the nomogram and risk score model performed well in the independent CGGA cohort. Gene set enrichment analysis (GSEA) and immune profile, drug sensitivity, and tumor mutation burden (TMB) analyses were performed in the two risk groups. A significant enrichment of ‘Autophagy–other’, ‘Collecting duct acid secretion’, ‘Glycosphingolipid biosynthesis–lacto and neolacto series’, ‘Valine, leucine, and isoleucine degradation’, ‘Vibrio cholerae infection’, and other pathways were observed for patients with high risk. In addition, higher proportions of monocytes and resting CD4 memory T cells were observed in the low- and high-risk groups, respectively. In conclusion, the BM-related gene risk score model can guide the clinical management of WHO grade II and III gliomas.

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Drug repositioning: Using psychotropic drugs for the treatment of glioma

Cited by 22 publications

References 85 publications

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

Novel small molecules inhibit proteotoxicity and inflammation: Mechanistic and therapeutic implications for Alzheimer’s Disease, healthspan and lifespan- Aging as a consequence of glycolysis

Basement-Membrane-Related Gene Signature Predicts Prognosis in WHO Grade II/III Gliomas

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