Gambogic acid potentiates clopidogrel-induced apoptosis and attenuates irinotecan-induced apoptosis through down-regulating human carboxylesterase 1 and -2
Abstract:1. In this study, we report that gambogic acid (GA), a promising anticancer agent, potentiates clopidogrel-induced apoptosis and attenuates CPT-11-induced apoptosis by down-regulating human carboxylesterase (CES) 1 and -2 via ERK and p38 MAPK pathway activation, which provides a molecular explanation linking the effect of drug combination directly to the decreased capacity of hydrolytic biotransformation. 2. The expression levels of CES1 and CES2 decreased significantly in a concentration- and time-dependent m… Show more
“…As depicted in Fig. 10 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 and ( Supplementary Information Table S3 ) 133 , 136 , some endogenous and exogenous substances have been confirmed with regulatory effects on the expression of mammalian CES. Treatment of mice with glucose could induce hepatic CE1 expression in vivo , due to glucose significantly activated the promoter activity of CES1 and increased acetylation of histone 3 and 4 in the CES1 chromatin 137 .…”
Section: Ces Inducersmentioning
confidence: 70%
“…In addition, urethane dimethacrylate (UDMA) was proved to induce the mRNA expression of CES2 in human dental pulp cells, without regulating the CES1 or CES3 mRNA expression 138 . In addition, gambogic acid decreased the protein expression of CES1 and CES2 via a dose-dependent manner, and the hydrolytic activities of CES1 and CES2 were also significantly decreased upon addition of gambogic acid 139 . Figure 10 Inducers of CES.…”
Mammalian carboxylesterases (CEs) are key enzymes from the serine hydrolase superfamily. In the human body, two predominant carboxylesterases (CES1 and CES2) have been identified and extensively studied over the past decade. These two enzymes play crucial roles in the metabolism of a wide variety of endogenous esters, ester-containing drugs and environmental toxicants. The key roles of CES in both human health and xenobiotic metabolism arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the efficacy of ester drugs. This review covers the structural and catalytic features of CES, tissue distributions, biological functions, genetic polymorphisms, substrate specificities and inhibitor properties of CES1 and CES2, as well as the significance and recent progress on the discovery of CES modulators. The information presented here will help pharmacologists explore the relevance of CES to human diseases or to assign the contribution of certain CES in xenobiotic metabolism. It will also facilitate medicinal chemistry efforts to design prodrugs activated by a given CES isoform, or to develop potent and selective modulators of CES for potential biomedical applications.
“…As depicted in Fig. 10 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 and ( Supplementary Information Table S3 ) 133 , 136 , some endogenous and exogenous substances have been confirmed with regulatory effects on the expression of mammalian CES. Treatment of mice with glucose could induce hepatic CE1 expression in vivo , due to glucose significantly activated the promoter activity of CES1 and increased acetylation of histone 3 and 4 in the CES1 chromatin 137 .…”
Section: Ces Inducersmentioning
confidence: 70%
“…In addition, urethane dimethacrylate (UDMA) was proved to induce the mRNA expression of CES2 in human dental pulp cells, without regulating the CES1 or CES3 mRNA expression 138 . In addition, gambogic acid decreased the protein expression of CES1 and CES2 via a dose-dependent manner, and the hydrolytic activities of CES1 and CES2 were also significantly decreased upon addition of gambogic acid 139 . Figure 10 Inducers of CES.…”
Mammalian carboxylesterases (CEs) are key enzymes from the serine hydrolase superfamily. In the human body, two predominant carboxylesterases (CES1 and CES2) have been identified and extensively studied over the past decade. These two enzymes play crucial roles in the metabolism of a wide variety of endogenous esters, ester-containing drugs and environmental toxicants. The key roles of CES in both human health and xenobiotic metabolism arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the efficacy of ester drugs. This review covers the structural and catalytic features of CES, tissue distributions, biological functions, genetic polymorphisms, substrate specificities and inhibitor properties of CES1 and CES2, as well as the significance and recent progress on the discovery of CES modulators. The information presented here will help pharmacologists explore the relevance of CES to human diseases or to assign the contribution of certain CES in xenobiotic metabolism. It will also facilitate medicinal chemistry efforts to design prodrugs activated by a given CES isoform, or to develop potent and selective modulators of CES for potential biomedical applications.
“…Consistent with this function, both IPAH/HPAH PAEC and iPSC-EC transfected with KISS1 siRNA versus scrambled siRNA show enhanced migration ( Figure 4D; see Figure E6B). Carboxylesterase 1 (CES1), a metabolizing enzyme suppressed by cancer therapy in association with induction of apoptosis (24), was down-regulated in IPAH/HPAH PAEC and iPSC-EC. CES1 siRNA in control cells reproduced the propensity to apoptosis seen in I/HPAH PAEC and iPSC-EC ( Figure 4E; see Figure E7C).…”
Section: Rna-seq Analysis Of Paec and Ipsc-ec From Patients With Ipahmentioning
Rationale: Idiopathic or heritable pulmonary arterial hypertension is characterized by loss and obliteration of lung vasculature. Endothelial cell dysfunction is pivotal to the pathophysiology, but different causal mechanisms may reflect a need for patient-tailored therapies.Objectives: Endothelial cells differentiated from induced pluripotent stem cells were compared with pulmonary arterial endothelial cells from the same patients with idiopathic or heritable pulmonary arterial hypertension, to determine whether they shared functional abnormalities and altered gene expression patterns that differed from those in unused donor cells. We then investigated whether endothelial cells differentiated from pluripotent cells could serve as surrogates to test emerging therapies.Methods: Functional changes assessed included adhesion, migration, tube formation, and propensity to apoptosis. Expression of bone morphogenetic protein receptor type 2 (BMPR2) and its target, collagen IV, signaling of the phosphorylated form of the mothers against decapentaplegic proteins (pSMAD1/5), and transcriptomic profiles were also analyzed.Measurements and Main Results: Native pulmonary arterial and induced pluripotent stem cell-derived endothelial cells from patients with idiopathic and heritable pulmonary arterial hypertension compared with control subjects showed a similar reduction in adhesion, migration, survival, and tube formation, and decreased BMPR2 and downstream signaling and collagen IV expression. Transcriptomic profiling revealed high kisspeptin 1 (KISS1) related to reduced migration and low carboxylesterase 1 (CES1), to impaired survival in patient cells. A beneficial angiogenic response to potential therapies, FK506 and Elafin, was related to reduced slit guidance ligand 3 (SLIT3), an antimigratory factor.Conclusions: Despite the site of disease in the lung, our study indicates that induced pluripotent stem cell-derived endothelial cells are useful surrogates to uncover novel features related to disease mechanisms and to better match patients to therapies.
“…Thus, CEs could serve as important determinants for pharmacokinetics and pharmacodynamics of ester drugs or ester prodrugs, such as irinotecan. Regulation of CEs is also involved in gambogic acid-induced cell apoptosis in cancer cells, CPT-11-related drug resistance, capecitabine-related toxicity, and inhibition of tumor growth . Understanding the behavior and regulation of CEs in various diseases is very beneficial for manipulating the disease pathology and clinical drug usage.…”
Carboxylesterases
(CEs) exist as multiple types of isomers in humans,
and two major types are CE1 and CE2. They are widely distributed in
human tissues and well-known for their important roles in drug metabolism
and pathology of various diseases. Thus, the detection of CEs in living
systems could provide efficient proof in disease diagnostics, as well
as important information regarding chemotherapeutic effects of antitumor
drugs and prognosis. To develop a specific probe to discriminate CEs
from other hydrolases, especially cholinesterases, is quite challenging
due to their structural similarities and substrate specificity. To
date, almost all of the fluorescent probes developed for CEs have
been constructed with an acetyl group as the recognition unit. Herein
we proposed a new design strategy of probe–cavity matching,
which led to the identification of a new fluorogenic substrate (termed
as HBT-CE) with high specificity toward both CE isomers and improved
sensitivity, considering the higher binding affinity and catalysis
efficiency. The promising capability of HBT-CE was further demonstrated
for endogenous CEs imaging in living cells, zebrafish, and nude mice.
In addition, HBT-CE was successfully applied in kinetically monitoring
drug-induced CE regulation in cancer cells. All of these findings
suggest that HBT-CE is a valuable tool for tracking and imaging endogenous
CEs in complex biological systems.
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