Amalgamation of PI3K and EZH2 blockade synergistically regulates invasion and angiogenesis: combination therapy for glioblastoma multiforme

Mishra, Vishnu S.; Kumar, Naveen; Raza, Masoom; Sehrawat, Seema

doi:10.18632/oncotarget.27842

Cited by 8 publications

(6 citation statements)

References 76 publications

(82 reference statements)

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“…E2 failed to induce proliferation, migration, and invasion when EZH2 was silenced or inhibited pharmacologically in U251 cells, suggesting that EZH2 mediates E2 effects on GBM cell lines. Although it has been previously reported that inhibition of EZH2 suppressed GBM growth, migration, and reversed EMT in vitro and in vivo (24,(43)(44)(45), this study is the first description demonstrating that EZH2 mediates E2 pro-oncogenic actions on GBM cells. Our results contribute to understanding the molecular mechanisms underlying GBM progression induced by E2 and EZH2 epigenetic mechanisms' participation.…”

Section: Discussionmentioning

confidence: 60%

EZH2 Mediates Proliferation, Migration, and Invasion Promoted by Estradiol in Human Glioblastoma Cells

et al. 2022

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Glioblastomas (GBM) are the most frequent and aggressive brain tumors. 17β-estradiol (E2) increases proliferation, migration, and invasion of human GBM cells; however underlying mechanisms are no fully understood. Zeste 2 Enhancer Homologous enzyme (EZH2) is a methyltransferase part of Polycomb 2 repressor complex (PRC2). In GBM, EZH2 is overexpressed and involved in the cell cycle, migration, and invasion processes. We studied the role of EZH2 in the pro-oncogenic actions of E2 in human GBM cells. EZH2 gene silencing and pharmacological inhibition of EZH2 blocked proliferation, migration, and invasion of GBM cells induced by E2. We identified in silico additional putative estrogen response elements (EREs) at the EZH2 promoter, but E2 did not modify EZH2 expression. In silico analysis also revealed that among human GBM samples, EZH2 expression was homogeneous; in contrast, the heterogeneous expression of estrogen receptors (ERs) allowed the classification of the samples into groups. Even in the GBM cluster with high expression of ERs and those of their target genes, the expression of PCR2 target genes did not change. Overall, our data suggest that in GBM cells, pro-oncogenic actions of E2 are mediated by EZH2, without changes in EZH2 expression and by mechanisms that appear to be unrelated to the transcriptional activity of ERs.

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Section: Discussionmentioning

confidence: 60%

EZH2 Mediates Proliferation, Migration, and Invasion Promoted by Estradiol in Human Glioblastoma Cells

et al. 2022

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“…The glioblastoma tumor microenvironment exhibits characteristic vascularization mediated by various growth factors and conditions. GBM U87 cells secrete particular growth factors that cause neo-angiogenesis in pre-existing capillaries ( 49 ). We analyzed the effect of CPI444 and vatalanib loaded GO-PEG on the angiogenic potential of GBM U87.…”

Section: Resultsmentioning

confidence: 99%

Combinatorial delivery of CPI444 and vatalanib loaded on PEGylated graphene oxide as an effective nanoformulation to target glioblastoma multiforme: In vitro evaluation

et al. 2022

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Glioblastoma multiforme (GBM) is known as the primary malignant and most devastating form of tumor found in the central nervous system of the adult population. The active pharmaceutical component in current chemotherapy regimens is mostly hydrophobic and poorly water-soluble, which hampers clinical implications. Nanodrug formulations using nanocarriers loaded with such drugs assisted in water dispersibility, improved cellular permeability, and drug efficacy at a low dose, thus adding to the overall practical value. Here, we successfully developed a water-dispersible and biocompatible nanocargo (GO-PEG) based on covalently modified graphene oxide (GO) with a 6-armed poly(ethylene glycol) amine dendrimer for effective loading of the two hydrophobic anticancer drug molecules, CPI444 and vatalanib. These drug molecules target adenosine receptor (A2AR), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and type III stem cell receptor tyrosine kinase (c-KIT), which plays a crucial role in cancers. The effective cellular delivery of the drugs when loaded on GO-PEG is attributed to the increased permeability of the drug-nanoconjugate formulation. We observed that this combinatorial drug treatment with nanocargo resulted in a significant reduction in the overall cell survival as supported by reduced calcium levels and stem cell markers such as Oct4 and Nanog, which are two of the prime factors for GBM stem cell proliferation. Furthermore, reduced expression of CD24 upon treatment with nanoformulation impeded cellular migration. Cellular assays confirmed inhibition of cell proliferation, migration, and angiogenic potential of GBM treated with GO-PEG–Drug conjugates. Ultimately, GBM U87 cells assumed programmed cell death at a very low concentration due to nanocarrier-mediated drug delivery along with the chosen combination of drugs. Together, this study demonstrated the advantage of GO-PEG mediated combined delivery of CPI444 and vatalanib drugs with increased permeability, a three-pronged combinatorial strategy toward effective GBM treatment.

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“…Methyl 3′-(N-Benzyl-2,4-bis(benzyloxy)-5-isopropylbenzamido)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-[1,1′-biphenyl]-3-carboxylate (33). Intermediate 33 was synthesized in 69% yield from starting material 21 using benzyl bromide in a manner similar to that described for compound 26.…”

Section: Methyl 3′-(24-bis(benzyloxy)-5-isopropyl-n-propylbenzamido)-...mentioning

confidence: 99%

“…EZH2, a crux subunit of the Polycomb Repressive Complex (PRC2), is responsible for methylating lysine 27 (mono-, di-, and trimethylation) in histone H3 (H3K27) and H3K27me3 is more frequently interlinked with transcriptional repression. − Notably, EZH2 is overexpressed in cancer stem cells of malignant tumors and plays a critical role in cancer stem cell expansion and maintenance. − Several key revelations ascertain the involvement of EZH2 in GBM initiation and progression, such as (i) involvement of miR-206/Twist axis in EZH2-regulated malignancy of GBM cells, (ii) pro-oncogenic actions of Estradiol (proliferation, migration, and invasion) by EZH2 in GBM cells, and (iii) direct transcriptional regulation of c-myc by EZH2 leading to the maintenance of GSCs . To validate EZH2 as a therapeutic target in GBM and capitalize on the aforementioned revelations, several EZH2 inhibitors (Figure ) were evaluated (monotherapy/combination therapy) − and optimistic results were attained, for instance, (i) GSK343, a highly potent and selective EZH2 inhibitor, demonstrated the ability to counteract GBM progression via modulation of canonical/noncanonical NF -κB/IκBα pathways and immune response; (ii) a cocktail of tazemetostat (EZH2 inhibitor) and PI-103 (PI3K inhibitor) exerted significant reduction in GBM progression (U-87 cells); (iii) HOTAIR-EZH2 inhibitor AC1Q3QWB in combination with GSK-LSD1 inhibitor elicited enhanced antitumor efficacy in GBM patient-derived xenograft (PDX) models; (iv) combination of HOTAIR-EZH2 inhibitor (AQB) and palbociclib inhibitors suppressed the cell cycle in gliomas with high expression of EZH2 and low expression of CWF19L1; and (v) treatment with EZH2 inhibitors MC4040 and MC4041 led to impairment of primary GBM cell viability and weakened the aggressive malignant phenotype by reducing angiogenesis …”

Section: Introductionmentioning

confidence: 99%

First-in-Class Dual EZH2-HSP90 Inhibitor Eliciting Striking Antiglioblastoma Activity In Vitro and In Vivo

Sharma,

Wang,

Yang

et al. 2024

J. Med. Chem.

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Structural analysis of tazemetostat, an FDA-approved EZH2 inhibitor, led us to pinpoint a suitable site for appendage with a pharmacophoric fragment of second-generation HSP90 inhibitors. Resultantly, a magnificent dual EZH2/HSP90 inhibitor was pinpointed that exerted striking cell growth inhibitory efficacy against TMZ-resistant Glioblastoma (GBM) cell lines. Exhaustive explorations of chemical probe 7 led to several revelations such as (i) compound 7 increased apoptosis/necrosis-related gene expression, whereas decreased M phase/kinetochore/spindle-related gene expression as well as CENPs protein expression in Pt3R cells; (ii) dual inhibitor 7 induced cell cycle arrest at the M phase; (iii) compound 7 suppressed reactive oxygen species (ROS) catabolism pathway, causing the death of TMZ-resistant GBM cells; and (iv) compound 7 elicited substantial in vivo anti-GBM efficacy in experimental mice xenografted with TMZ-resistant Pt3R cells. Collectively, the study results confirm the potential of dual EZH2-HSP90 inhibitor 7 as a tractable anti-GBM agent.

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Amalgamation of PI3K and EZH2 blockade synergistically regulates invasion and angiogenesis: combination therapy for glioblastoma multiforme

Cited by 8 publications

References 76 publications

EZH2 Mediates Proliferation, Migration, and Invasion Promoted by Estradiol in Human Glioblastoma Cells

EZH2 Mediates Proliferation, Migration, and Invasion Promoted by Estradiol in Human Glioblastoma Cells

Combinatorial delivery of CPI444 and vatalanib loaded on PEGylated graphene oxide as an effective nanoformulation to target glioblastoma multiforme: In vitro evaluation

First-in-Class Dual EZH2-HSP90 Inhibitor Eliciting Striking Antiglioblastoma Activity In Vitro and In Vivo

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