产品号 #73592_C
Epigenetic modifier; Inhibits histone methyltransferases SU(VAR)3-9
概述
Chaetocin is a fungal mycotoxin, originally produced by Chaetomium species, that inhibits the lysine-specific histone methyltransferases (HMTs) SU(VAR)3-9 (IC₅₀ = 0.8 μM). HMTs are responsible for methylation of histones, thereby affecting heterochromatinization. Chaetocin is also known to inhibit G9a and DIM5 (IC₅₀ = 2.5 μM and 3 μM respectively; Cherblanc et al.; Greiner et al.). Chaetocin also acts as a competitive substrate and inhibitor of the central oxidative stress remediation enzyme thioredoxin reductase-1 (TrxR1; Km = 4.6 μM) more potently than glutathione reductase or thioredoxin (Tibodeau et al.).
CANCER RESEARCH
· Induces cellular oxidative stress, selectively killing cancer cells and rapidly-proliferating primary cells (Isham et al.; Spannhoff et al.)
· Attenuates the growth of glioma xenografts accompanied by an increase in reactive oxygen species (ROS) production (Dixit et al.).
Cell Type
Cancer Cells and Cell Lines
Species
Human, Mouse, Non-Human Primate, Other, Rat
Area of Interest
Cancer
CAS Number
28097-03-2
Chemical Formula
C₃₀H₂₈N₆O₆S₄
Purity
≥ 95%
Pathway
Epigenetic
Target
Histone Methyltransferase
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
Resources and Publications
Publications (6)
Chaetocin-induced ROS-mediated apoptosis involves ATM-YAP1 axis and JNK-dependent inhibition of glucose metabolism. Cell death & disease 2014 JAN
Abstract
Oxidative stress serves as an important regulator of both apoptosis and metabolic reprogramming in tumor cells. Chaetocin, a histone methyltransferase inhibitor, is known to induce ROS generation. As elevating basal ROS level sensitizes glioma cells to apoptosis, the ability of Chaetocin in regulating apoptotic and metabolic adaptive responses in glioma was investigated. Chaetocin induced glioma cell apoptosis in a ROS-dependent manner. Increased intracellular ROS induced (i) Yes-associated protein 1 (YAP1) expression independent of the canonical Hippo pathway as well as (ii) ATM and JNK activation. Increased interaction of YAP1 with p73 and p300 induced apoptosis in an ATM-dependent manner. Chaetocin induced JNK modulated several metabolic parameters like glucose uptake, lactate production, ATP generation, and activity of glycolytic enzymes hexokinase and pyruvate kinase. However, JNK had no effect on ATM or YAP1 expression. Coherent with the in vitro findings, Chaetocin reduced tumor burden in heterotypic xenograft glioma mouse model. Chaetocin-treated tumors exhibited heightened ROS, pATM, YAP1 and pJNK levels. Our study highlights the coordinated control of glioma cell proliferation and metabolism by ROS through (i) ATM-YAP1-driven apoptotic pathway and (ii) JNK-regulated metabolic adaptation. The elucidation of these newfound connections and the roles played by ROS to simultaneously shift metabolic program and induce apoptosis could provide insights toward the development of new anti-glioma strategies.
Chaetocin is a nonspecific inhibitor of histone lysine methyltransferases. Nature chemical biology 2013 MAR
Abstract
The anticancer agent chaetocin is a competitive substrate and inhibitor of thioredoxin reductase. Antioxidants & redox signaling 2009 MAY
Abstract
We recently reported that the antineoplastic thiodioxopiperazine natural product chaetocin potently induces cellular oxidative stress, thus selectively killing cancer cells. In pursuit of underlying molecular mechanisms, we now report that chaetocin is a competitive and selective substrate for the oxidative stress mitigation enzyme thioredoxin reductase-1 (TrxR1) with lower K(m) than the TrxR1 native substrate thioredoxin (Trx; chaetocin K(m) = 4.6 +/- 0.6 microM, Trx K(m) = 104.7 +/- 26 microM), thereby attenuating reduction of the critical downstream ROS remediation substrate Trx at achieved intracellular concentrations. Consistent with a role for TrxR1 targeting in the anticancer effects of chaetocin, overexpression of the TrxR1 downstream effector Trx in HeLa cells conferred resistance to chaetocin-induced, but not to doxorubicin-induced, cytotoxicity. As the TrxR/Trx pathway is of central importance in limiting cellular reactive oxygen species (ROS)--and as chaetocin exerts its selective anticancer effects via ROS imposition--the inhibition of TrxR1 by chaetocin has potential to explain its selective anticancer effects. These observations have important implications not just with regard to the mechanism of action and clinical development of chaetocin and related thiodioxopiperazines, but also with regard to the utility of molecular targets within the thioredoxin reductase/thioredoxin pathway in the development of novel candidate antineoplastic agents.
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