BIX-01294, a G9a inhibitor, suppresses cell proliferation by inhibiting autophagic flux in nasopharyngeal carcinoma cells

Li, Qian; Wang, Liuqian; Ji, Di; Bao, Xiaomin; Tan, Guojing; Liang, Xiaojun; Deng, Ping; Pi, Huifeng; Lu, Yonghui; Chen, Chunhai; He, Mindi; Zhang, Lei; Zhou, Zhou; Yu, Zhengping; Deng, Anchun

doi:10.1007/s10637-020-01053-7

Cited by 5 publications

(3 citation statements)

References 30 publications

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Section: Resultsmentioning

confidence: 99%

“…This drug selectively impairs the G9a HMTase and also shows inhibitory activity towards the nuclear receptor binding SET Domain Protein 1 (NSD1), a bifunctional transcriptional regulatory protein that encodes a histone methyltransferase that is mutated in several tumors, including pancreatic cancer [29]. Its antitumoral effect was also described in nasopharyngeal carcinoma, ovarian cancer, or cholangiocarcinoma, either alone or in combination with other therapies [30][31][32]. Analyzing the half-maximal inhibitory concentration (IC50) (Supplementary Table S1), the triple epigenetic inhibitor UVI5008 showed the highest effect in all pancreatic cell lines tested, similar to previous reports on leukemia, colon, prostate, and breast tumor models, with a good safety profile in mice [28].…”

Section: Effect Of Epigenetic Inhibitors and P53r3 On The Viability O...mentioning

confidence: 99%

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Synergistic Antitumoral Effect of Epigenetic Inhibitors and Gemcitabine in Pancreatic Cancer Cells

et al. 2022

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Epigenetic modifications could drive some of the molecular events implicated in proliferation, drug resistance and metastasis of pancreatic ductal adenocarcinoma (PDAC). Thus, epigenetic enzyme inhibitors could be the key to revert those events and transform PDAC into a drug-sensitive tumor. We performed a systematic study with five different epigenetic enzyme inhibitors (1, UVI5008, MS275, psammaplin A, and BIX01294) targeting either Histone Deacetylase (HDAC) 1 or 1/4, DNA methyltransferase 3a (DNMT3a), Euchromatic histone lysine methyltransferase 2 (EHMT2), or Sirtuin 1 (SIRT1), as well as one drug that restores the p53 function (P53R3), in three different human PDAC cell lines (SKPC-1, MIA PaCa-2, and BxPC-3) using 2D and 3D cell cultures. The synergistic effect of these antitumoral drugs with gemcitabine was tested and the most efficient combinations were characterized by RNA-seq. The inhibition of HDAC1/4 (MS275), HDAC1/4/SIRT1/DNMT3a (UVI5008) or EHMT2 (BIX01294) induced a significant reduction on the cell viability, even in gemcitabine-resistance cells. The combination of UVI5008 or MS275 with gemcitabine induced a synergistic effect at low concentration and the RNA-Seq analysis revealed some synergy candidate genes as potential biomarkers. Reverting aberrant epigenetic modifications in combination with gemcitabine offers an alternative treatment for PDAC patients, with an important reduction of the therapeutic dose.

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Section: Resultsmentioning

confidence: 99%

Section: Effect Of Epigenetic Inhibitors and P53r3 On The Viability O...mentioning

confidence: 99%

Synergistic Antitumoral Effect of Epigenetic Inhibitors and Gemcitabine in Pancreatic Cancer Cells

et al. 2022

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“…Recent studies have shown that BIX-01294 can repress tumor growth in NPCs (nasopharyngeal carcinoma cells) and OSCC (oral squamous cells carcinoma) by regulating caspase-independent apoptotic pathways and suppressing autophagic flux. G9a inhibition by BIX-01294 helps in reducing corneal angiogenesis by blocking the production of Nox-4 (NADPH oxidase 4) dependent reactive oxygen species (Li et al, 2021). Treatment with BIX-01294 was demonstrated to inhibit tumor growth in leukemia cell lines HL-60 and NB4 (Savickiene et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Effect of Inhibitor UNC0642 on Expression of G9a and Its Proliferative and Apoptotic Markers in Breast Cancer Cell Line MCF-7

Yaqub¹,

Amin²,

Fatima³

et al. 2022

PJZ

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G9a is a lysine methyltransferase that has been reported to downregulate the expression of tumor suppressor genes in a variety of cancerous cells. The present study explores the anti-cancer activity of UNC0642, a novel potent inhibitor of G9a in MCF-7 breast cancer cell line. Analysis of growth and proliferation parameters by various cell-based assays such as neutral red assay and BrdU cell proliferation assay showed that higher concentrations were lethal for the cancerous cells. IC 50 was found to be 12.6 µM. Further contextualization of the therapeutic potential of G9a inhibition was provided by expression analysis of the G9a gene and genes associated with cell proliferation, tumor suppression, and apoptosis. The gene expression of fibroblast growth factor 1 (FGF1), enolase 2 (ENO2), cyclin D1 (CCND1), catalytic subunit of AMP-activated protein kinase (AMPKα2), RNA polymerase II transcription elongation factor (ELL2), and pro-apoptotic Bcl-2 homology 3-only protein (BIM) in MCF-7 breast cancer and normal human embryonic kidney HEK-293 cell lines were studied in response to treatment with different concentrations of UNC0642. Inhibition of G9a expression was observed in a dose-dependent manner in both cell lines with increasing UNC0642 concentrations. A dose-dependent downregulation of gene expression of proliferation marker genes (FGF-1, CCND1, and ENO2) was observed in both cell lines, whereas upregulation of tumor suppressor genes (AMPKα2 and ELL2) and apoptotic marker gene (BIM) was observed in a dose-dependent manner. Taken together, the results indicated the potential of G9a inhibition in the reduction of cancerous cell proliferation and inducing apoptosis in cancerous cells. Further elucidation of the signaling pathways associated with G9a, in-vitro and in-vivo safety analyses is required to fully establish G9a as a therapeutic target for cancer progression and UNC0642 as an anticancerous therapeutic agent for the treatment of breast cancer.

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The role of histone methylation in renal cell cancer: an update

Hou

Yuan

et al. 2022

Mol Biol Rep

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BIX-01294, a G9a inhibitor, suppresses cell proliferation by inhibiting autophagic flux in nasopharyngeal carcinoma cells

Cited by 5 publications

References 30 publications

Synergistic Antitumoral Effect of Epigenetic Inhibitors and Gemcitabine in Pancreatic Cancer Cells

Synergistic Antitumoral Effect of Epigenetic Inhibitors and Gemcitabine in Pancreatic Cancer Cells

Effect of Inhibitor UNC0642 on Expression of G9a and Its Proliferative and Apoptotic Markers in Breast Cancer Cell Line MCF-7

The role of histone methylation in renal cell cancer: an update

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