Evidence map›Paper›PMID 31791385›Full record

ArticleClinical epigenetics2019

Dissecting the role of novel EZH2 inhibitors in primary glioblastoma cell cultures: effects on proliferation, epithelial-mesenchymal transition, migration, and on the pro-inflammatory phenotype.

Giulia Stazi, Ludovica Taglieri, Alice Nicolai, Annalisa Romanelli, Rossella Fioravanti, Stefania Morrone, Manuela Sabatino, Rino Ragno, Samanta Taurone, Marcella Nebbioso and 5 more

RetractedOpen access · goldAbstract readRetracted Publication
PubMed Full text at PMC Publisher
In one paragraph

Article in Clinical epigenetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It has been retracted, and should not be counted. Cited by 35 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
35citing papers in PubMed, 1 pooled it
3.3field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

35 citing papers in PubMed, 1 synthesis or guideline pooled it, 61 citations in OpenAlex.

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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

15 authors at 1 institution in 1 country.

Giulia StaziDepartment of Chemistry and Technologies of Drugs, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.
Ludovica TaglieriDepartment of Experimental Medicine, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.
Alice NicolaiDepartment of Experimental Medicine, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.
Annalisa RomanelliDepartment of Chemistry and Technologies of Drugs, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.
Rossella FioravantiDepartment of Chemistry and Technologies of Drugs, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.
Stefania MorroneDepartment of Experimental Medicine, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.
Manuela SabatinoAlchemical Dynamics s.r.l, 00125, Roma, Italy.
Rino RagnoDepartment of Chemistry and Technologies of Drugs, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.
Samanta TauroneDepartment of Sense Organs, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.
Marcella NebbiosoDepartment of Sense Organs, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.
Raffaella CarlettiDepartment of Radiologic, Oncological, and Anatomical and Pathological Sciences, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.
Marco ArticoDepartment of Sense Organs, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.
Sergio ValenteDepartment of Chemistry and Technologies of Drugs, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy. sergio.valente@uniroma1.it.
Susanna ScarpaDepartment of Experimental Medicine, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy. susanna.scarpa@uniroma1.it.
Antonello MaiDepartment of Chemistry and Technologies of Drugs, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy. antonello.mai@uniroma1.it.ORCID 0000-0001-9176-2382
Sapienza University of Rome · IT

Funding

Histone Lysine deMethylation: Structures, Inhibitions and MechanismsR01GM114306 · NIGMS · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI CHENG, XIAODONG · 2015 to 2018
$1.2M
NIGMS NIH HHS R01 GM114306
6 · The paper itself

Abstract

backgroundGlioblastoma (GBM) is the most lethal and aggressive malignant primary brain tumor in adults. After surgical resection of the tumor, the patient typically should be subjected to chemotherapy (temozolomide, TMZ) and concomitant radiotherapy. Since the TMZ treatment does not lead to complete remission and often develops resistance, the identification of efficacious therapeutics is strongly to pursue. Among the epigenetic players, the H3K27 methyltransferase (MT) EZH2 (enhancer of zeste homologue 2) has been found overexpressed or mutated in several human cancers including gliomas, and its overexpression is associated with poor outcome in GBM. Two EZH2 inhibitors (EZH2i), UNC1999 and GSK343, suppressed GBM growth in vitro and in vivo indicating that EZH2i can be potential drugs against GBM.

resultsTwo new EZH2i, MC4040 and MC4041, were designed, prepared, and tested by us to determine their effects in primary GBM cell cultures. MC4040 and MC4041 displayed single-digit micromolar inhibition of EZH2, 10-fold less potency against EZH1, and no activity towards other MTs. In primary GBM cells as well as in U-87 GBM cells, the two compounds reduced H3K27me3 levels, and dose- and time-dependently impaired GBM cell viability without inducing apoptosis and arresting the cell cycle in the G0/G1 phase, with increased p21 and p27 levels. In combination with TMZ, MC4040 and MC4041 displayed stronger, but not additive, effects on cell viability. The potent clinical candidate as EZH2i tazemetostat, alone or in combination with TMZ, exhibited a similar potency of inhibition of GBM cell growth when compared to MC4040 and MC4041. At the molecular level, MC4040 and MC4041 reduced the VEGFR1/VEGF expression, reversed the epithelial-mesenchymal transition (EMT), and hampered cell migration and invasion attenuating the cancer malignant phenotype. Treatment of GBM cells with MC4040 and MC4041 also impaired the GBM pro-inflammatory phenotype, with a significant decrease of TGF-β, TNF-α, and IL-6, joined to an increase of the anti-inflammatory cytokine IL-10.

conclusionsThe two novel EZH2i MC4040 and MC4041 impaired primary GBM cell viability, showing even stronger effects in combination with TMZ. They also weakened the aggressive malignant phenotype by reducing angiogenesis, EMT, cell migration/invasion and inflammation, thus they may be considered potential candidates against GBM also for combination therapies.

Indexed as

Brain NeoplasmsCell MovementCell ProliferationCell SurvivalCytokinesDose-Response Relationship, DrugEnhancer of Zeste Homolog 2 ProteinEnzyme InhibitorsEpigenesis, GeneticEpithelial-Mesenchymal TransitionGene Expression Regulation, NeoplasticGlioblastomaHumansPrimary Cell CultureTemozolomideTime FactorsCytokinesEnhancer of Zeste Homolog 2 ProteinEnzyme InhibitorsEZH2 protein, humanTemozolomideEMTEpigeneticsEZH2GlioblastomaHistone methylationInflammation

Identifiers

PMID31791385
PMCPMC6889222
OpenAlexW2990022892

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.