Identification of Chaetocin as a Potent non-ROS-mediated Anticancer Drug Candidate for Gastric Cancer

Liao, Xian; Fan, Yaqiong; Hou, Jihuan; Xiong, Chen; Xu, Xiaolin; Yang, Yifan; Shen, Jinying; Mi, Panying; Huang, Xiaohua; Zhang, Wenqing; Cao, Hanwei; Hong, Xin; Hu, Tianhui; Zhan, Yan-yan

doi:10.7150/jca.32803

Cited by 15 publications

(7 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, the number of LC3 dots and the expression levels of autophagy-related genes were increased by chaetocin, indicating that chaetocin induces autophagic activity in porcine SCNT embryos. These results are consistent with previous reports that chaetocin induces autophagic activity by increasing the LC3 level in cancer cells [ 58 , 59 ]. Moreover, the expression level of most maternal-related genes was higher in SCNT than in IVF embryos but was decreased by chaetocin.…”

Section: Discussionsupporting

confidence: 94%

Chaetocin Improves Pig Cloning Efficiency by Enhancing Epigenetic Reprogramming and Autophagic Activity

Jeong

Sim

Park

et al. 2020

IJMS

View full text Add to dashboard Cite

Efficient epigenetic reprogramming is crucial for the in vitro development of mammalian somatic cell nuclear transfer (SCNT) embryos. The aberrant levels of histone H3 lysine 9 trimethylation (H3K9me3) is an epigenetic barrier. In this study, we evaluated the effects of chaetocin, an H3K9me3-specific methyltransferase inhibitor, on the epigenetic reprogramming and developmental competence of porcine SCNT embryos. The SCNT embryos showed abnormal levels of H3K9me3 at the pronuclear, two-cell, and four-cell stages compared to in vitro fertilized embryos. Moreover, the expression levels of H3K9me3-specific methyltransferases (suv39h1 and suv39h2) and DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) were higher in SCNT embryos. Treatment with 0.5 nM chaetocin for 24 h after activation significantly increased the developmental competence of SCNT embryos in terms of the cleavage rate, blastocyst formation rate, hatching rate, cell number, expression of pluripotency-related genes, and cell survival rate. In particular, chaetocin enhanced epigenetic reprogramming by reducing the H3K9me3 and 5-methylcytosine levels and restoring the abnormal expression of H3K9me3-specific methyltransferases and DNA methyltransferases. Chaetocin induced autophagic activity, leading to a significant reduction in maternal mRNA levels in embryos at the pronuclear and two-cell stages. These findings revealed that chaetocin enhanced the developmental competence of porcine SCNT embryos by regulating epigenetic reprogramming and autophagic activity and so could be used to enhance the production of transgenic pigs for biomedical research.

show abstract

Section: Discussionsupporting

confidence: 94%

Chaetocin Improves Pig Cloning Efficiency by Enhancing Epigenetic Reprogramming and Autophagic Activity

Jeong

Sim

Park

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Results for all compounds are representative of three independent biological replicates with technical triplicates (n = 3, IC 50 ± SEM) unless otherwise indicated as represented by a "not determined". a Activity data of the compounds on various mammalian lines were collated from previous reports15,21,41,49,[65][66][67][68][69][70][71] .…”

mentioning

confidence: 99%

Epigenetic inhibitors target multiple stages of Plasmodium falciparum parasites

Coetzee

Grüning

Opperman

et al. 2020

Sci Rep

View full text Add to dashboard Cite

The epigenome of the malaria parasite, Plasmodium falciparum, is associated with regulation of various essential processes in the parasite including control of proliferation during asexual development as well as control of sexual differentiation. The unusual nature of the epigenome has prompted investigations into the potential to target epigenetic modulators with novel chemotypes. Here, we explored the diversity within a library of 95 compounds, active against various epigenetic modifiers in cancerous cells, for activity against multiple stages of P. falciparum development. We show that P. falciparum is differentially susceptible to epigenetic perturbation during both asexual and sexual development, with early stage gametocytes particularly sensitive to epi-drugs targeting both histone and nonhistone epigenetic modifiers. Moreover, 5 compounds targeting histone acetylation and methylation show potent multistage activity against asexual parasites, early and late stage gametocytes, with transmission-blocking potential. Overall, these results warrant further examination of the potential antimalarial properties of these hit compounds. The almost inevitable development of drug resistance in malaria parasites enforces continued discovery of novel classes of antimalarial compounds 1. To contribute to global malaria elimination strategies, such compounds would need to target multiple life cycle stages of the parasite 2. This includes targeting the rapidly dividing (~48 h) asexual parasites to reduce parasite burden, as well as targeting mature, terminally differentiated sexual gametocytes to block onward human-to-mosquito transmission of the parasite, or exo-erythrocytic liver stage development to block mosquito-to-human transmission. Importantly, to prolong or prevent resistance development, new chemical matter should target novel biological activities in the parasite 3. In oncology research, epigenetic therapeutics ('epi-drugs') evidently hold great promise as targets for anticancer therapies 4 , with several drugs approved for clinical use, including Azacitidine, Decitabine, Vorinostat and Romidepsin 5. The antitumor activity is ascribed to epigenetic deregulation as a result of inhibition of epigenetic modulators, including histone modifying enzymes and DNA methyltransferases. This results in particular changes in histone post-translational modifications (PTMs), disruption of transcriptional processes, chromatin structure maintenance and DNA repair 6,7. Plasmodium falciparum relies heavily on epigenetic mechanisms to drive both asexual proliferation and sexual differentiation (reviewed in 8-11). The parasite's genome encodes a unique complement of histone modifying enzymes including histone deacetylases (HDACs), histone acetyltransferases (HATs), histone methyltransferases (HMTs, including lysine HKMT), protein arginine methyltransferases (PRMTs), and histone demethylases (HDMs) 12 in addition to other non-histone epigenetic modifiers. As a result, inhibitors of histone modifying enzymes have been investigated as no...

show abstract

“…Autophagy plays a controversial role in cancer development and has been widely discussed during the past decade [ 34 , 35 ]. Some of the autophagy-related genes have been shown to be promising treatment targets [ 14 , 36 , 37 ]. However, the expression of these autophagy genes in stratifying the prognostic risk in GBM patients is still unclear.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel autophagy-related prognostic signature and small molecule drugs for glioblastoma by bioinformatics

et al. 2022

View full text Add to dashboard Cite

Objective To explore the autophagy-related prognostic signature (ARPs) via data mining in gene expression profiles for glioblastoma (GBM). Methods Using the Cancer Genome Atlas (TCGA) database, we obtained 156 GBM samples and 5 adjacent normal samples, and denoted them as discovery cohort. Univariate Cox regression analysis was used to screen autophagy genes that related to GBM prognosis. Then, the least absolute shrinkage and selection operator Cox regression model was used to construct an autophagy-based ARPs, which was validated in an external cohort containing 80 GBM samples. The patients in the above-mentioned cohorts were divided into low-risk group and high-risk group according to the median prognostic risk score, and the diagnostic performance of the model was assessed by receiver operating characteristic curve analyses. The gene ontology and Kyoto encyclopedia of genes and genomes pathway enrichment analyses were performed between the high-risk and low-risk patients. Additionally, the genetic features of ARPs, such as genetic variation profiles, correlations with tumor-infiltrating lymphocytes (TILs), and potential drug sensitivity, were further assessed in the TCGA-GBM data set. Results A signature of ARPs including NDUFB9, BAK1, SUPT3H, GAPDH, CDKN1B, CHMP6, and EGFR were detected and validated. We identified a autophagy-related prognosis 7-gene signature correlated survival prognosis, immune infiltration, level of cytokines, and cytokine receptor in tumor microenvironment. Furthermore, the signature was tested in several pathways related to disorders of tumor microenvironment, as well as cancer-related pathways. Additionally, a range of small molecular drugs, shown to have a potential therapeutic effect on GBM. Conclusions We constructed an autophagy-based 7-gene signature, which could serve as an independent prognostic indicator for cases of GBM and sheds light on the role of autophagy as a potential therapeutic target in GBM.

show abstract

Identification of Chaetocin as a Potent non-ROS-mediated Anticancer Drug Candidate for Gastric Cancer

Cited by 15 publications

References 36 publications

Chaetocin Improves Pig Cloning Efficiency by Enhancing Epigenetic Reprogramming and Autophagic Activity

Chaetocin Improves Pig Cloning Efficiency by Enhancing Epigenetic Reprogramming and Autophagic Activity

Epigenetic inhibitors target multiple stages of Plasmodium falciparum parasites

Identification of a novel autophagy-related prognostic signature and small molecule drugs for glioblastoma by bioinformatics

Contact Info

Product

Resources

About