Novel cytokine release inhibitors. Part I: Triterpenes

Huang, Fu‐Chih; Chan, Wan-Kit; Moriarty, K.J.M.; Zhang, Decheng; Chang, Ming‐Wen; He, Wei; Yu, Kin‐Tak; Zilberstein, Asher

doi:10.1016/s0960-894x(98)00331-x

Cited by 37 publications

(30 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, celastrol's elevation of GR levels supports its useful anti-inflammation effects (Huang et al 1998), while celastrol's down-regulation effects on AR and the elevation effect on P53 back up celastrol as a useful prostate cancer inhibitor in vitro and in vivo (Pang et al 2010;Yang et al 2006). Even the effect of ER elevation adds rationale to celastrol's role in treating neuron degenerative disease (Faust et al 2009;Kiaei et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Celastrol regulates multiple nuclear transcription factors belonging to HSP90's clients in a dose- and cell type-dependent way

Zhang

Cao

et al. 2010

Cell Stress and Chaperones

View full text Add to dashboard Cite

Celastrol, a novel HSP90 inhibitor, has recently attracted much attention due to its potential in multiple applications, such as anti-inflammation use, degenerative neuron disease relief, and tumor management. At present, the studies in celastrol's effects on HSP90's clients have focused on the kinase sub-population, while another key sub-population, nuclear transcription factors (TFs), is not being well-explored. In this study, we observe the effects of celastrol on 18 TFs (belonging to HSP90 clients) in three human cell lines: MCF-7 (breast cancer), HepG2 (hepatoma), and THP-1 (monocytic leukemia). The results show that at least half of the detectable TFs were affected by celastrol, though the effect patterns varied with cell type and dosage. Bi-directional regulations of some TFs were identified, a phenomenon not yet seen with other HSP90 inhibitors. Celastrol's capability to affect multiple TFs was consistent with its altering HSP90/TFs interactions and disrupting HSP90/Hop interaction, in addition to the reported damaging HSP90/Cdc37 interaction. This work confirms, for the first time, that celastrol has broad effects on TFs belonging to HSP90's clients, casts new light on understanding these reported actions, and suggests new possible applications for celastrol, such as diabetes management.

show abstract

Section: Discussionmentioning

confidence: 99%

Celastrol regulates multiple nuclear transcription factors belonging to HSP90's clients in a dose- and cell type-dependent way

Zhang

Cao

et al. 2010

Cell Stress and Chaperones

View full text Add to dashboard Cite

show abstract

“…17 The downregulation of these adhesion molecules by celastrol is most likely due to the suppression of NF-B activity as reported here. The down-regulation of inflammatory cytokines 14,15 and iNOS 16 also could be due to modulation of NF-B activation.…”

Section: Discussionmentioning

confidence: 99%

“…10 Celastrol is also known to inhibit the proliferation of a variety of tumor cells, including those from leukemia, 11 gliomas, 12 and prostate cancer. 13 The ability of celastrol to modulate the expression of proinflammatory cytokines, 3,14,15 MHC-II antigen, 6 inducible nitric oxide (NO) synthase (iNOS), 16 adhesion molecules in endothelial cells, 17 proteasome activity, 13 topoisomerase II, 11 potassium channels, 18 and heat shock response 19 has been reported. However, the molecular mechanism underlying the anti-inflammatory and antiproliferative effects of celastrol is not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-κB–regulated gene products and TAK1-mediated NF-κB activation

Sethi

Ahn

Pandey

et al. 2006

Blood

308

242

View full text Add to dashboard Cite

Celastrol, a quinone methide triterpene derived from the medicinal plant Tripterygium wilfordii, has been used to treat chronic inflammatory and autoimmune diseases, but its mechanism is not well understood. Therefore, we investigated the effects of celastrol on cellular responses activated by TNF, a potent proinflammatory cytokine. Celastrol potentiated the apoptosis induced by TNF and chemotherapeutic agents and inhibited invasion, both regulated by NF-B activation. We found that TNF induced the expression of gene products involved in antiapoptosis (IAP1, IAP2, Bcl-2, Bcl-X L , c-FLIP, and survivin), proliferation (cyclin D1 and COX-2), invasion (MMP-9), and angiogenesis (VEGF) and that celastrol treatment suppressed their expression. Because these gene products are regulated by NF-B, we postulated that celastrol mediates its effects by modulating the NF-B pathway. We found that celastrol suppressed both inducible and constitutive NF-B activation. Celastrol was found to inhibit the TNF-induced activation of I B␣ kinase, I B␣ phosphorylation, I B␣ degradation, p65 nuclear trans- IntroductionModern targeted therapies for most chronic illnesses, including cancer, have been mostly unsuccessful because of their ineffectiveness, lack of safety, and cost. Although monotherapy was advocated at one time, recent experience indicates that agents that target multiple pathways have more potential in cancer treatment. This understanding has led to combination therapy. Although traditional therapies have been around for thousands of years, their active components and their mechanisms of action remain undefined. Identification of an active chemical entity and its molecular targets can lead to rediscovery of the clinical potential of such therapies, as in the case of paclitaxel, derived from Taxus (yew) species during a random screening of US Department of Agriculture collection of plants. 1 Celastrol, also known as tripterine, is one such compound that was originally identified from traditional Chinese medicine ("God of Thunder Vine") almost 3 decades ago and used for the treatment of cancer and other inflammatory diseases. 2 Celastrol, a triterpenoid from the Celastracae family and extracted from the plant Tripterygium wilfordii, 3 has attracted interest, especially for its potential anti-inflammatory effects. 4 The in vivo anti-inflammatory effects of this triterpene have been demonstrated in animal models of collagen-induced arthritis, 5 Alzheimer disease, 6 asthma, 7 systemic lupus erythematosus, 8,9 and rheumatoid arthritis. 10 Celastrol is also known to inhibit the proliferation of a variety of tumor cells, including those from leukemia, 11 gliomas, 12 and prostate cancer. 13 The ability of celastrol to modulate the expression of proinflammatory cytokines, 3,14,15 6 inducible nitric oxide (NO) synthase (iNOS), 16 adhesion molecules in endothelial cells, 17 proteasome activity, 13 topoisomerase II, 11 potassium channels, 18 and heat shock response 19 has been reported. However, the molecular mechanism underlying the ...

show abstract

“…Proinflammatory cytokines and lymphocytes: Celastrol (65) has been found to reduce levels of cytokines including IL-1α and IL-1β (Lei and Li, 1991;Li et al, 1997;Takaishi et al, 1997;Huang et al, 1998), IL-2 (Lei and Li, 1991;Xu et al, 1991;Li et al, 1997), IL-6, IL-8 (He et al, 1998;Pinna et al, 2004), and TNF-α (Allison et al, 2001;Pinna et al, 2004). It also reduced antibody formation in mice (Lei and Li, 1991).…”

mentioning

confidence: 99%

“…There are conflicting reports as to whether 65 reduces cytokine production by inhibiting synthesis, or by inhibiting posttranslational processing/secretion Pinna et al, 2004). Tingenone (=tingenin A, maytenin) (66), 22β-hydroxytingenone (=tingenin B) (67), and 64 also inhibited IL-1β production; 67 inhibited synthesis of IL-1α as well Huang et al, 1998).…”

mentioning

confidence: 99%

Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae)

et al. 2007

View full text Add to dashboard Cite

Plants in the genus Tripterygium, such as Tripterygium wilfordii Hook. f., have a long history of use in traditional Chinese medicine. In recent years there has been considerable interest in the use of Tripterygium extracts and of the main bioactive constituent, the diterpene triepoxide triptolide (1), to treat a variety of autoimmune and inflammation-related conditions. The main mode of action of the Tripterygium extracts and triptolide (1) is the inhibition of expression of proinflammatory genes such as those for interleukin-2 (IL-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and interferon-gamma (IFN-γ). The efficacy and safety of certain types of Tripterygium extracts were confirmed in human clinical trials in the US and abroad. Over 300 compounds have been identified in the genus Tripterygium, and many of these have been evaluated for biological activity. The overall activity of the extract is based on the interaction between its components. Therefore, the safety and efficacy of the extract cannot be fully mimicked by any individual constituent. This review discusses the biochemical composition and biological and pharmacological activities of Tripterygium extracts, and their main bioactive components.

show abstract

Novel cytokine release inhibitors. Part I: Triterpenes

Cited by 37 publications

References 20 publications

Celastrol regulates multiple nuclear transcription factors belonging to HSP90's clients in a dose- and cell type-dependent way

Celastrol regulates multiple nuclear transcription factors belonging to HSP90's clients in a dose- and cell type-dependent way

Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-κB–regulated gene products and TAK1-mediated NF-κB activation

Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae)

Contact Info

Product

Resources

About