EZH2, HIF-1, and Their Inhibitors: An Overview on Pediatric Cancers

Papale, M.; Ferretti, Elisabetta; Battaglia, Giuseppe; Bellavia, Diana; Mai, Antonello; Tafani, Marco

doi:10.3389/fped.2018.00328

Cited by 16 publications

(13 citation statements)

References 85 publications

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“…Another possible way to modulate HIF-1 activity is the disruption of protein stabilization and accumulation. Hsp90 inhibitors, such as geldanamycin, tanespimycin, and alvespimycin, degrade HIF-1α through a VHL-independent proteasomal mechanism [ 91 , 92 , 93 ]. Moreover, histone deacetylase inhibitors (HDACi), such as vorinostat exerted anti-hypoxic activity by degrading the HIF-1α subunit in liver cancer-derived cells [ 94 ].…”

Section: Hypoxic Conditionsmentioning

confidence: 99%

Flavonoids Targeting HIF-1: Implications on Cancer Metabolism

Samec

Líšková

Koklesová

et al. 2021

Cancers

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Tumor hypoxia is described as an oxygen deprivation in malignant tissue. The hypoxic condition is a consequence of an imbalance between rapidly proliferating cells and a vascularization that leads to lower oxygen levels in tumors. Hypoxia-inducible factor 1 (HIF-1) is an essential transcription factor contributing to the regulation of hypoxia-associated genes. Some of these genes modulate molecular cascades associated with the Warburg effect and its accompanying pathways and, therefore, represent promising targets for cancer treatment. Current progress in the development of therapeutic approaches brings several promising inhibitors of HIF-1. Flavonoids, widely occurring in various plants, exert a broad spectrum of beneficial effects on human health, and are potentially powerful therapeutic tools against cancer. Recent evidences identified numerous natural flavonoids and their derivatives as inhibitors of HIF-1, associated with the regulation of critical glycolytic components in cancer cells, including pyruvate kinase M2(PKM2), lactate dehydrogenase (LDHA), glucose transporters (GLUTs), hexokinase II (HKII), phosphofructokinase-1 (PFK-1), and pyruvate dehydrogenase kinase (PDK). Here, we discuss the results of most recent studies evaluating the impact of flavonoids on HIF-1 accompanied by the regulation of critical enzymes contributing to the Warburg phenotype. Besides, flavonoid effects on glucose metabolism via regulation of HIF-1 activity represent a promising avenue in cancer-related research. At the same time, only more-in depth investigations can further elucidate the mechanistic and clinical connections between HIF-1 and cancer metabolism.

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Section: Hypoxic Conditionsmentioning

confidence: 99%

Flavonoids Targeting HIF-1: Implications on Cancer Metabolism

Samec

Líšková

Koklesová

et al. 2021

Cancers

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“…Effectiveness of these compounds have been noted to vary depending on factors such as the EZH status (mutation and/or protein expression), type of the tumor, and the status of other disease markers [64]. Targeting EZH2 by small molecule inhibitors has also been thought to be an attractive strategy in new therapeutics development for refractory pediatric tumors.…”

Section: Combination Of Ezh2 Inhibitors and Selinexor Resulted In Uprmentioning

confidence: 99%

Targeting EZH2-mediated methylation of histone 3 inhibits proliferation of pediatric acute monocytic leukemia cells in vitro

Ghabkari

Narendran

2021

Preprint

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Background: Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and a catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the mono-, di-, and tri-methylation of histone H3 at Lys 27 (H3K27me3) to facilitate chromatin remodeling and gene silencing functions. The overexpression of EZH2 is associated with high levels of H3K27me3 in various types of cancers. Previous reports showed a significant association of EZH2 aberrations in pediatric cancers such as soft tissue sarcomas and glioblastoma. Recent reports in human subjects and animal models have also suggested a central role of EZH2 in the induction and progression of acute myeloid leukemia. Methods: In this study, we aimed to investigate the molecular status of EZH in cell lines derived from distinct pediatric leukemia to assess the efficacy of targeting EZH2 to suppress cancer cell survival and proliferation. Cell cytotoxicity and the half maximal inhibitory concentration (IC50) were measured by Alamar blue cytotoxicity assay. The molecular status of EZH2 was profiled by DNA sequencing and western blot analysis of EZH2 protein levels in THP-1, SEM, and MV4:11. In addition, Methylation of histone H3 was evaluated by immunoblotting and immunostaining analyses. Results: Our results showed that EZH2 protein is overexpressed in the pediatric monocytic cell line THP-1 , but not in other leukemia derived cell lines MV4;11 and SEM. Screening a panel of methyltransferase inhibitors revealed that three inhibitors; GSK126, UNC1999 and EPZ-5687 are the most potent inhibitors that suppressed EZH2 activity selectively on lysine 27 which resulted in increased apoptosis and inhibition of AKT and ERK protein phosphorylation in THP-1 cells. Our data demonstrated a significant increase in apoptosis in cells treated with drug combination (EZH2i and selinexor) compared to EZH2i inhibitors alone. Conclusions: Taken together, our data provide initial evidence that targeting EZH2 is a promising therapeutic strategy for the treatment of subtypes of pediatric AML. Also, combining EZH2 inhibitors with selinexor may increase the treatment efficacy in these patients. Findings from this study indicate further evaluation and consideration of these compounds for early phase clinical studies in selected pediatric malignancies in the future.

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“…Another target gene of HIF-1 α is the VEGF one. VEGF expression is modulated by HIF-1 α (42) and it is a key pro-angiogenic step for tumor progression. Moreover, pazopanib is able to block the VEGF signaling through the tyrosin kinase inhibition of VEGFR-2 (43).…”

Section: Discussionmentioning

confidence: 99%

Effects of Pazopanib Monotherapy vs. Pazopanib and Topotecan Combination on Anaplastic Thyroid Cancer Cells

et al. 2019

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The purpose of this study was to examine pazopanib/topotecan combination activity vs. pazopanib monotherapy on anaplastic thyroid cancer (ATC) cells. Proliferation analyses were performed on ATC cell lines administered for 72 h with pazopanib and topotecan alone and to their simultaneous combination. Pazopanib and topotecan produced a strong synergism on ATC cells, calculated by the combination index, increasing the intracellular concentrations of topotecan lactone measured by high-performance liquid chromatography. Furthermore, a significantly decrease of the gene expression of ATP-binding cassette transporter G2 (ABCG-2), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1α (HIF-1α), and colony stimulating factor-1 (CSF-1) was presented in combination-treated ATC cells by real time PCR tests. In summary, the simultaneous association of pazopanib and topotecan established a highly synergistic ATC antiproliferative effect, suggesting a new possibility to translate this schedule into clinical trials.

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EZH2, HIF-1, and Their Inhibitors: An Overview on Pediatric Cancers

Cited by 16 publications

References 85 publications

Flavonoids Targeting HIF-1: Implications on Cancer Metabolism

Flavonoids Targeting HIF-1: Implications on Cancer Metabolism

Targeting EZH2-mediated methylation of histone 3 inhibits proliferation of pediatric acute monocytic leukemia cells in vitro

Effects of Pazopanib Monotherapy vs. Pazopanib and Topotecan Combination on Anaplastic Thyroid Cancer Cells

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