Medicinal Compound Celastrol As a Potential Clinical Anticancer Drug: Lessons Learned From Preclinical Studies

Wu, Jianquan; Hong, Chengcheng; Pan, Hongjie; Yang, Qingzhu; Yu, Mei; Dou, Q. Ping; Yang, Huanjie

doi:10.2174/2212697x03666160112001739

Cited by 4 publications

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“…Despite its potential therapeutic effects, there are still some limitations to the use of celastrol, such as its low solubility results in poor bioavailability, in vitro and in vivo toxicity, and adverse effects that remain to be evaluated (J. Wu et al, 2016 ; T. Zhang et al, 2008 ). Celastrol was not cytotoxic to all cell lines tested herein, even at the highest concentration (1000 nM), corroborating other reports using Caco‐2 cells (Z. Wang et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

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Celastrol: A lead compound that inhibits SARS‐CoV‐2 replication, the activity of viral and human cysteine proteases, and virus‐induced IL‐6 secretion

Fuzo

Martins

Fraga-Silva

et al. 2022

Drug Development Research

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The global emergence of coronavirus disease 2019 (COVID‐19) has caused substantial human casualties. Clinical manifestations of this disease vary from asymptomatic to lethal, and the symptomatic form can be associated with cytokine storm and hyperinflammation. In face of the urgent demand for effective drugs to treat COVID‐19, we have searched for candidate compounds using in silico approach followed by experimental validation. Here we identified celastrol, a pentacyclic triterpene isolated from Tripterygium wilfordii Hook F, as one of the best compounds out of 39 drug candidates. Celastrol reverted the gene expression signature from severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐infected cells and irreversibly inhibited the recombinant forms of the viral and human cysteine proteases involved in virus invasion, such as M pro (main protease), PL pro (papain‐like protease), and recombinant human cathepsin L. Celastrol suppressed SARS‐CoV‐2 replication in human and monkey cell lines and decreased interleukin‐6 (IL‐6) secretion in the SARS‐CoV‐2‐infected human cell line. Celastrol acted in a concentration‐dependent manner, with undetectable signs of cytotoxicity, and inhibited in vitro replication of the parental and SARS‐CoV‐2 variant. Therefore, celastrol is a promising lead compound to develop new drug candidates to face COVID‐19 due to its ability to suppress SARS‐CoV‐2 replication and IL‐6 production in infected cells.

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Section: Discussionmentioning

confidence: 99%

Section: Celastrol Inhibits the Activity Of Papain Hcatl And The Sars...mentioning

confidence: 99%

Celastrol: A lead compound that inhibits SARS‐CoV‐2 replication, the activity of viral and human cysteine proteases, and virus‐induced IL‐6 secretion

Fuzo

Martins

Fraga-Silva

et al. 2022

Drug Development Research

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show abstract

“…Despite its potential therapeutic effects, there are still some limitations to the use of celastrol, such as its low solubility that results in poor bioavailability, in vitro and in vivo toxicity, and adverse effects that remain to be evaluated 107,108 . Celastrol was not cytotoxic to all cell lines tested herein, even at the highest concentration (1000 nM), corroborating other reports using Caco-2 cells 109 .…”

Section: Discussionmentioning

confidence: 99%

Drug repurposing to face Covid-19: Celastrol, a potential leading drug capable of inhibiting SARS-CoV-2 replication and induced inflammation

Fuzo

Martins

Fraga-Silva

et al. 2021

Preprint

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The global emergence of Covid-19 has caused huge human casualties. Clinical manifestations of the disease vary from asymptomatic to lethal, and the symptomatic form can be associated with cytokine storm and non-homeostatic inflammatory response. In face of the urgent demand for effective drugs to treat Covid-19, we have searched for candidate compounds using a drug repurposing approach based on in silico analysis followed by biological validation. Here we identified celastrol, a pentacyclic triterpene isolated from Tripterygium wilfordii Hook F – a plant used in traditional Chinese medicine – as one of the best compounds out of 39 repurposed drug candidates. Celastrol reverted gene expression signature from SARS-CoV-2-infected cells; bound with high-affinity energy to viral molecular targets such as main protease (Mpro) and receptor-biding domain (RBD); inhibited SARS-CoV-2 replication in monkey (Vero and Vero-ACE2) and human (Caco-2 and Calu-3) cell lines; and decreased interleukin-6 (IL-6) secretion in SARS-CoV-2-infected human cell lines. Interestingly, celastrol acted in a concentration-dependent manner, with undetectable signs of cytotoxicity. Therefore, celastrol is a promising lead drug candidate to treat Covid-19 due to its ability to suppress SARS-CoV-2 replication and IL-6 production in infected cells, two critical events in the pathophysiology of this disease.

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“…In recent years, celastrol has attracted considerable interest because of its substantial therapeutic properties in the treatment of multiple diseases, including obesity, rheumatoid arthritis, allergic asthma, systemic lupus erythematosus, lateral sclerosis, and Alzheimer’s disease [11–13]. However, the most attractive function of celastrol is its potential antitumor effect, which has been demonstrated in a wide variety of cancer cell lines and in vivo in animal models [14–19]. The molecular mechanisms of the action of celastrol have been investigated, and they include modulating apoptosis, proliferation, angiogenesis, invasion, and metastasis [19–21].…”

Section: Introductionmentioning

confidence: 99%

Ferroptosis inducer erastin sensitizes NSCLC cells to celastrol through activation of the ROS–mitochondrial fission–mitophagy axis

et al. 2021

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Despite recent progress in non-small-cell lung cancer (NSCLC) treatment, treatment outcomes remain poor, mainly because of treatment resistance or toxicity. Erastin is a ferroptosis inducer that has shown promising cytotoxic effects in various types of cancers, including NSCLC. Celastrol is a triterpene extracted from the Tripterygium wilfordii that exhibits potential anticancer activity. However, the side effects of celastrol are severe and limit its clinical application. Combination therapy is a promising strategy to overcome the compensatory mechanisms and unwanted off-target effects. In the present study, we found that erastin synergized with celastrol to induce cell death at nontoxic concentrations. The combined treatment with celastrol and erastin significantly increased reactive oxygen species (ROS) generation, disrupted mitochondrial membrane potential, and promoted mitochondrial fission. Furthermore, cotreatment with erastin and celastrol initiated ATG5/ATG7-dependent autophagy, PINK1/Parkin-dependent mitophagy, and the expression of heat shock proteins (HSPs) in an HSF1-dependent manner. HSF1 knockdown further enhanced cell death in vitro and inhibited tumor growth in vivo. Our findings indicate that the combination of celastrol with erastin may represent a novel therapeutic regimen for patients with NSCLC and warrants further clinical evaluation.

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Medicinal Compound Celastrol As a Potential Clinical Anticancer Drug: Lessons Learned From Preclinical Studies

Cited by 4 publications

References 0 publications

Celastrol: A lead compound that inhibits SARS‐CoV‐2 replication, the activity of viral and human cysteine proteases, and virus‐induced IL‐6 secretion

Celastrol: A lead compound that inhibits SARS‐CoV‐2 replication, the activity of viral and human cysteine proteases, and virus‐induced IL‐6 secretion

Drug repurposing to face Covid-19: Celastrol, a potential leading drug capable of inhibiting SARS-CoV-2 replication and induced inflammation

Ferroptosis inducer erastin sensitizes NSCLC cells to celastrol through activation of the ROS–mitochondrial fission–mitophagy axis

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