Tackling the Behavior of Cancer Cells: Molecular Bases for Repurposing Antipsychotic Drugs in the Treatment of Glioblastoma

Persico, Michele; Abbruzzese, Claudia; Matteoni, Silvia; Matarrese, Paola; Campana, Anna Maria; Villani, Veronica; Pace, Andrea; Paggi, Marco G.

doi:10.3390/cells11020263

Cited by 13 publications

(19 citation statements)

References 154 publications

(207 reference statements)

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“…Drug repositioning has become a strategy to reduce time and costs, proposing new applications for known drugs. This strategy was recently applied to identify treatments for several diseases such as tumors ( Aydin et al, 2022 ; Persico et al, 2022 ; Petrosyan et al, 2022 ), cardiac diseases ( Rouhana et al, 2021 ), and neurodegenerative diseases ( Bhat et al, 2020 ; Agostini et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study

Antoniciello

Roncarati

Zannoni

et al. 2022

Front. Mol. Biosci.

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Antibiotic-resistant bacterial pathogens are a very challenging problem nowadays. Helicobacter pylori is one of the most widespread and successful human pathogens since it colonizes half of the world population causing chronic and atrophic gastritis, peptic ulcer, mucosa-associated lymphoid tissue-lymphoma, and even gastric adenocarcinoma. Moreover, it displays resistance to numerous antibiotics. One of the H. pylori pivotal transcription factors, HP1043, plays a fundamental role in regulating essential cellular processes. Like other bacterial transcription factors, HP1043 does not display a eukaryote homolog. These characteristics make HP1043 a promising candidate to develop novel antibacterial strategies. Drug repositioning is a relatively recent strategy employed in drug development; testing approved drugs on new targets considerably reduces the time and cost of this process. The combined computational and in vitro approach further reduces the number of compounds to be tested in vivo. Our aim was to identify a subset of known drugs able to prevent HP1043 binding to DNA promoters. This result was reached through evaluation by molecular docking the binding capacity of about 14,350 molecules on the HP1043 dimer in both conformations, bound and unbound to the DNA. Employing an ad hoc pipeline including MMGBSA molecular dynamics, a selection of seven drugs was obtained. These were tested in vitro by electrophoretic mobility shift assay to evaluate the HP1043–DNA interaction. Among these, three returned promising results showing an appreciable reduction of the DNA-binding activity of HP1043. Overall, we applied a computational methodology coupled with experimental validation of the results to screen a large number of known drugs on one of the H. pylori essential transcription factors. This methodology allowed a rapid reduction of the number of drugs to be tested, and the drug repositioning approach considerably reduced the drug design costs. Identified drugs do not belong to the same pharmaceutical category and, by computational analysis, bound different cavities, but all display a reduction of HP1043 binding activity on the DNA.

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Section: Discussionmentioning

confidence: 99%

Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study

Antoniciello

Roncarati

Zannoni

et al. 2022

Front. Mol. Biosci.

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“…Other non-oncological drugs being investigated as anti-glioma agents include various statins [ 160 ], metformin [ 161 , 162 ] and disulfiram [ 163 ] as well as drugs developed for treating various pathogens, such as mebendazole, chloroquine and lumefantrine [ 164 , 165 , 166 , 167 ]. CNS compounds under investigation include anti-schizophrenia drugs (fluphenazine and fluspirilene) [ 168 ] and anti-epileptics (valproic acid [ 169 ] and levetericam [ 170 , 171 ]) as well as drugs developed for Alzheimer’s (memantine) [ 172 ] or Parkinson’s disease (pimavanserin) [ 173 ] ( Table 1 ).…”

Section: Drug Repurposing For Glioblastomamentioning

confidence: 99%

Drug Repurposing, a Fast-Track Approach to Develop Effective Treatments for Glioblastoma

Ntafoulis

Koolen

Leenstra

et al. 2022

Cancers

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Glioblastoma (GBM) remains one of the most difficult tumors to treat. The mean overall survival rate of 15 months and the 5-year survival rate of 5% have not significantly changed for almost 2 decades. Despite progress in understanding the pathophysiology of the disease, no new effective treatments to combine with radiation therapy after surgical tumor debulking have become available since the introduction of temozolomide in 1999. One of the main reasons for this is the scarcity of compounds that cross the blood–brain barrier (BBB) and reach the brain tumor tissue in therapeutically effective concentrations. In this review, we focus on the role of the BBB and its importance in developing brain tumor treatments. Moreover, we discuss drug repurposing, a drug discovery approach to identify potential effective candidates with optimal pharmacokinetic profiles for central nervous system (CNS) penetration and that allows rapid implementation in clinical trials. Additionally, we provide an overview of repurposed candidate drug currently being investigated in GBM at the preclinical and clinical levels. Finally, we highlight the importance of phase 0 trials to confirm tumor drug exposure and we discuss emerging drug delivery technologies as an alternative route to maximize therapeutic efficacy of repurposed candidate drug.

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“…Drug repurposing, the discipline that discovers new applications for old drugs, allows effective medications to be brought from bench to bedside and seems applicable to GBM (9); antipsychotic drugs play an important role in this setting (10), also according to the recent identi cation of tumor-neuron synaptic connectivity through which GBM cells use neuromediators as oncogenic stimuli (11). Recently, we investigated the effect of the neuroleptic drug chlorpromazine (CPZ) in inhibiting several molecular and cellular parameters in GBM cells (12,13), thus paving the way for repurposing this drug in GBM therapy in combination with the rst-line therapeutic approach described in 2005 by Stupp et al (2).…”

Section: Introductionmentioning

confidence: 99%

Chlorpromazine affects glioblastoma bioenergetics by interfering with pyruvate kinase M2

Abbruzzese

Matteoni

Matarrese

et al. 2023

Preprint

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Glioblastoma (GBM) is the most frequent and lethal brain tumor, whose therapeutic outcome - only partially effective with current schemes - places this disease among the unmet medical needs, and effective therapeutic approaches are urgently required. In our attempts to identify repositionable drugs in glioblastoma therapy, we identified chlorpromazine (CPZ) as a very promising compound. Here we aimed to further unveil the mode of action of this drug. We performed a supervised recognition of the signal transduction pathways potentially influenced by CPZ via Reverse-Phase Protein microArrays (RPPA) and carried out an Activity-Based Protein Profiling (ABPP) followed by Mass Spectrometry (MS) analysis to possibly identify cellular factors targeted by the drug. Indeed, the glycolytic enzyme PKM2 was identified as a major target of CPZ. Furthermore, using the Seahorse platform, we analyzed the bioenergetics changes induced by the drug. CPZ hindered GBM anabolic pathways and stimulated autophagy. Consistent with the ability of CPZ to target PKM2, we detected relevant changes in GBM energy metabolism, possibly attributable to the drug’s ability to inhibit the oncogenic properties of PKM2. RPE-1 non-cancer neuroepithelial cells appeared resistant to the drug. PKM2 silencing reduced the effects of CPZ. 3D modeling showed that CPZ interacts with PKM2 tetramer in the same region involved in binding other known activators. The effect of CPZ can be epitomized as an inhibition of the Warburg effect and, thus, malignancy in GBM cells while sparing RPE-1 cells. These preclinical data enforce the rationale that allowed us to investigate the role of CPZ in GBM treatment in an ongoing multicenter Phase II clinical trial.

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Tackling the Behavior of Cancer Cells: Molecular Bases for Repurposing Antipsychotic Drugs in the Treatment of Glioblastoma

Cited by 13 publications

References 154 publications

Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study

Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study

Drug Repurposing, a Fast-Track Approach to Develop Effective Treatments for Glioblastoma

Chlorpromazine affects glioblastoma bioenergetics by interfering with pyruvate kinase M2

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