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Therapeutic Effects and Related Molecular Mechanisms of Celastrol, a Triterpenoid Natural Compound and Novel HSP90 Inhibitor Extracted from Plants of the Celastraceae Family

  • Bin Peng
  • Ying Wang
  • Yu-Ting Song
  • Xue Zhang
  • Fan-Fan Cao
  • Li-Min Xu
  • Mei Jiang
  • Xiao-Ling Bo
  • Georges Uzan
  • Deng-Hai Zhang
Chapter
Part of the Heat Shock Proteins book series (HESP, volume 19)

Abstract

Celastrol, a triterpenoid compound first identified in the Chinese herbal Tripterygium Wilfordii Hook, f. (TWHF), has attracted much attention in recent years due to its promise in multiple applications. Initially, celastrol was studied mainly as a toxic agent to treat cancer and inflammation. Celastrol’s potential applications have since expanded following findings that it could protect cells due to inducing heat shock proteins via HSF-1 activation (now attributed as caused by HSP90 inhibition). In this paper, we review the therapeutic effects of celastrol towards a variety of abnormalities demonstrated in animal models, including autoimmune and inflammatory diseases, various cancers, neurodegenerative issues, and chronic metabolic disorders. The cellular responses, signaling pathways and proteins reportedly affected by celastrol are also introduced. Moreover, based on celastrol’s chemical structure and properties, as well as reported findings, we present a new molecular model for celastrol’s direct inhibition of the HSP90 chaperone complex, which might be generalized to cover the interactions between celastrol and other targeted proteins. Finally, we suggest future work focusing on clinical translation.

Keywords

Cancer Celastrol Heat shock protein HSP90 inhibitor Hydrophobicity Inflammation Metabolic disease Michael addition Molecular docking Neurodegenerative disease NF-κB inhibitor 

Abbreviations

AKT

RAC-alpha serine/threonine-protein kinase

AML

Acute myeloid leukemia

AMPK

AMP-activated protein kinase

ATF2 or 6

Activating transcription factor 2 or 6

Cdc37

Cell division cycle 37

CDK

Cyclin-dependent kinase

c-Myc

Constitutively expressed homology with the viral gene v-myc

DSS

Dextran sodium sulfate

ERK

Extracellular signal-regulated kinase

HO-1

Heme oxygenase 1

HSF-1

Heat shock factor 1

HSP

Heat shock protein

HSR

Heat shock response

IKK

Inhibitor of nuclear factor kappa-B kinase

JNK

c-Jun N-terminal kinases

MAPK

Mitogen-activated protein kinase

MAX

Myc-associated factor X protein

MD2

Lymphocyte antigen 96

MMP-9

Matrix metallopeptidase 9

MnSOD

Manganese-dependent superoxide dismutase

MPO

Myeloperoxidase

mTOR

Mammalian target of rapamycin

NAD

Nicotinamide adenine dinucleotide

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

NLRP3

NACHT,LRR and PYD domains-containing protein 3

NO

Nitric oxide

Nrf2

Nuclear factor (erythroid-derived 2)-like 2

PERK

Protein kinase R (PKR)-like endoplasmic reticulum kinase

PGC1α

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PI3K

Phosphatidylinositol-4,5-bisphosphate 3-kinase

RANKL

Receptor activator of nuclear factor kappa-B ligand

ROS

Reactive oxygen species

SARM

Sterile α- and armadillo-motif-containing protein

STAT3

Signal transducer and activator of transcription 3

TGF-β1

Transforming growth factor beta 1

TLR4

Toll-like receptor 4

TNFα

Tumor necrosis factor alpha

Treg

Regulatory T cells

TWHF

Tripterygium Wilfordii Hook, f.

VEGF

Vascular endothelial growth factor

VEGFR

Vascular endothelial growth factor receptor

Notes

Acknowledgements

Thanks to Mr. Steven Schwab for tidying up the English expressions and grammar. This work was supported in part by the Foundation of Discipline Leader in Health Systems of the Pudong New District (No. PWRd2018-12), the National Natural Science Foundation of China (No. 81102349 and No. 81400793), Shanghai Traditional Chinese Medicine Content Construction Innovation Project (ZY3-CCCX-3-7001), Shanghai health and family planning commission General Program (No. 201540394 and No. 201540395), the Disciplines Group Construction Project of Pu Dong Health Bureau of Shanghai (No. PXZxq2017-15), the Shanghai Gongli Hospital Project (GLRb2018-01 and GLRq2017-01), and Postdoctoral Sustentation Fund of Shanghai Gongli Hospital (No. GLBH2017001).

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Bin Peng
    • 1
  • Ying Wang
    • 1
  • Yu-Ting Song
    • 1
    • 2
  • Xue Zhang
    • 1
  • Fan-Fan Cao
    • 1
  • Li-Min Xu
    • 1
  • Mei Jiang
    • 3
  • Xiao-Ling Bo
    • 4
  • Georges Uzan
    • 1
    • 5
  • Deng-Hai Zhang
    • 1
  1. 1.Sino-French Cooperative Lab, Shanghai Gongli HospitalThe Second Military Medical UniversityShanghaiChina
  2. 2.Postgraduate College of Ning Xiang Medical UniversityYinchuan CityChina
  3. 3.Department of Neurology, Shanghai Gongli HospitalThe Second Military Medical UniversityShanghaiChina
  4. 4.Department of Dermatology, Shanghai Gongli HospitalThe Second Military Medical UniversityShanghaiChina
  5. 5.Inserm 1197 Research Unit, Universite Paris Sud, Paris-Saclay UniversityVillejuifFrance

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