Metabolomics Reveals that Cysteine Metabolism Plays a Role in Celastrol-Induced Mitochondrial Apoptosis in HL-60 and NB-4 Cells

Chen, Minjian; Yang, Jing; Li, Lei; Hu, Yanhui; Lü, Xiaomei; Sun, Rongli; Wang, Yubang; Wang, Xinru

doi:10.1038/s41598-019-57312-y

Cited by 10 publications

(7 citation statements)

References 55 publications

(62 reference statements)

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“…Therefore, an appropriate design of CEL in light of the pivotal binding site might be able to enhance its activity and target selectivity. In addition, Chen et al reported that a decrease in the metabolites involved in cysteine metabolism was the key metabolic change after CEL treatment . The CEL derivatives (including 9 ) might show the same activity.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Novel Celastrol–Imidazole Derivatives with Anticancer Activity In Vitro and In Vivo

Zhang

et al. 2022

J. Med. Chem.

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To discover celastrol (CEL) derivatives with enhanced Hsp90–Cdc37 inhibition, C-20-COOH was introduced with various substituted imidazoles, which might affect the Michael addition of CEL by nucleophilic attack. The most potent compound 9, which showed higher antiproliferation, covalent-binding ability, and Hsp90–Cdc37 inhibition than CEL, was selected from 28 new target compounds. Then, the binding sites and the docking mode of 9 to Hsp90 and Cdc37 were studied. Furthermore, the activity of 9 sharply decreased or even disappeared in the Hsp90- and/or Cdc37-overexpressing A549 cells, indicating that the activity was related to its combination with Hsp90 and Cdc37. Moreover, 9 could more effectively induce apoptosis and inhibit tumor growth than CEL in vivo. This study first found that imidazoles linked to C-20 of CEL might affect its Michael addition, which will provide support of CEL or even the other Michael acceptors for the development as antitumor agents.

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Section: Discussionmentioning

confidence: 99%

Discovery of Novel Celastrol–Imidazole Derivatives with Anticancer Activity In Vitro and In Vivo

Zhang

et al. 2022

J. Med. Chem.

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“…The triterpenes contained in Tw HF are mainly divided into the friedelane, oleanane, and ursane types of chemical constituents, which prominently exhibit anti‐inflammatory, anticancer, antiviral, antifibrotic, immunosuppressive, metabolic dysfunction regulation, and spermicidal activities 20,22,37,39‐46 . In particular, celastrol, the first constituent isolated from Tw HF, belongs to the group of friedelane‐type triterpenes and is considered to be one of the main active and promising constituents.…”

Section: Chemical Constituents Bioactivities and Quality Controlmentioning

confidence: 99%

Tripterygium wilfordii: An inspiring resource for rheumatoid arthritis treatment

Zhang

Mao

et al. 2020

Medicinal Research Reviews

103

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Tripterygium wilfordii Hook F (TwHF)‐based therapy is among the most efficient and crucial therapeutics for the treatment of rheumatoid arthritis (RA), which indicates that TwHF is a potential source of novel anti‐RA drugs. However, accumulating studies have observed that TwHF‐based therapy induces multi‐organ toxicity, which prevents the wide use of this herb in clinical practice, although several recent studies have attempted to reduce the toxicity of TwHF. Notably, our research group developed a “Clinical Practice Guideline for Tripterygium Glycosides/Tripterygium wilfordii Tablets in the Treatment of Rheumatoid Arthritis” (No. T/CACM 1337‐2020) approved by the China Association of Chinese Medicine to standardize the clinical application of TwHF‐based therapy and thus avoid adverse effects. Although great strides have been made toward the characterization of TwHF‐based therapy and revealing its underlying pharmacological and toxicological mechanisms, several crucial gaps in knowledge remain as potential barriers to enhance its therapeutic effects on the premise of safety assurance. This review offers a global view of TwHF, ranging from its chemical constituents, quality control, clinical observations, and underlying pharmacological mechanisms to toxic manifestations and mechanisms. We focus on the important and emerging aspects of this field and highlight the major challenges and strategies for using novel techniques and approaches to gain new insights into unresolved questions. We hope that this review will improve the understanding of TwHF application and draw increasing interdisciplinary attention from clinicians that practice both Chinese and Western medicine, basic researchers, and computer scientists.

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“…We now consider the lipophilic triterpenoid quinonemethide celastrol (Figure 4), also known as tripterine, isolated from the traditional Chinese medicinal plant léi gōng téng 雷公藤 or Thunder of God vine (Tripterygium wilfordii) as the redox component (Chen et al, 2018). Celastrol exhibits potent antitumour and other biological activities that involve inter alia redox activity associated with generation of intracellular ROS and modulation of downstream signalling pathways (Moreira et al, 2019;Peng et al, 2019;Chen et al, 2020;Lu et al, 2021;Youns et al, 2021). Celastrol also inhibits the flavoenzyme siderophore A that catalyzes the hydroxylation of L-ornithine in Apergillis fumigatus.…”

Section: Introductionmentioning

confidence: 99%

“…Thus far, the antimalarial MoA has not been elucidated. However, it is clear that the redox-active quinone methide moiety of celastrol bestows overall biological activity (Kucera et al, 2013;Moreira et al, 2019;Peng et al, 2019;Chen et al, 2020;Lu et al, 2021;Youns et al, 2021). In this sense, this aspect correlates with the antimalarial activities of MB and redox-active naphthoquinones such as menadione (Lanfranchi et al, 2012;Klotz et al, 2014) that are active against asexual and sexual blood stage parasites (Gupta et al, 2002;Tanaka et al, 2015;Ehrhardt et al, 2016;Sidorov et al, 2016;Ahenkorah et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Antimalarial and antitumour activities of the steroidal quinone-methide celastrol and its combinations with artemiside, artemisone and methylene blue

Han

et al. 2022

Front. Pharmacol.

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Artemisinin, isolated from the traditional Chinese medicinal plant qīng hāo 青蒿 (Artemisia annua) and its derivatives are used for treatment of malaria. With treatment failures now being recorded for the derivatives and companion drugs used in artemisinin combination therapies new drug combinations are urgently required. The amino-artemisinins artemiside and artemisone display optimal efficacies in vitro against asexual and sexual blood stages of the malaria parasite Plasmodium falciparum and are active against tumour cell lines. In continuing the evolution of combinations of the amino-artemisinins with new drugs, we examine the triterpenoid quinone methide celastrol isolated from the traditional Chinese medicinal plant léi gōng téng 雷公藤 (Tripterygium wilfordii). This compound is redox active, and has attracted considerable attention because of potent biological activities against manifold targets. We report that celastrol displays good IC50 activities ranging from 0.50–0.82 µM against drug-sensitive and resistant asexual blood stage Pf, and 1.16 and 0.28 µM respectively against immature and late stage Pf NF54 gametocytes. The combinations of celastrol with each of artemisone and methylene blue against asexual blood stage Pf are additive. Given that celastrol displays promising antitumour properties, we examined its activities alone and in combinations with amino-artemisinins against human liver HepG2 and other cell lines. IC50 values of the amino-artemisinins and celastrol against HepG2 cancer cells ranged from 0.55–0.94 µM. Whereas the amino-artemisinins displayed notable selectivities (SI > 171) with respect to normal human hepatocytes, in contrast, celastrol displayed no selectivity (SI < 1). The combinations of celastrol with artemiside or artemisone against HepG2 cells are synergistic. Given the promise of celastrol, judiciously designed formulations or structural modifications are recommended for mitigating its toxicity.

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Metabolomics Reveals that Cysteine Metabolism Plays a Role in Celastrol-Induced Mitochondrial Apoptosis in HL-60 and NB-4 Cells

Cited by 10 publications

References 55 publications

Discovery of Novel Celastrol–Imidazole Derivatives with Anticancer Activity In Vitro and In Vivo

Discovery of Novel Celastrol–Imidazole Derivatives with Anticancer Activity In Vitro and In Vivo

Tripterygium wilfordii: An inspiring resource for rheumatoid arthritis treatment

Antimalarial and antitumour activities of the steroidal quinone-methide celastrol and its combinations with artemiside, artemisone and methylene blue

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