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Triptolide and celastrol are predominantly active natural products isolated from the medicinal plant
Several classes of bioactive substances have been isolated and characterized from TWHF, including sesquiterpenes, diterpenes (triptolide, tripdiolide, and triptonide), triterpenes (celastrol, pristimerin, and wilforlide A), lignans, glycosides, and alkaloids (
Pharmacological activities of triptolide and celastrol
Disease model | Natural product | Animal model | Experimental detail | Outcome of the study | Reference |
---|---|---|---|---|---|
RA | Triptolide | Bovine type II collagen-induced RA in male SD rats | 30 μg/kg ( |
Downregulation of RANKL-mediated ERK/AKT signaling pathway | |
Celastrol | Freund’s complete adjuvant-induced RA in C57BL/6 mice | 0.5 mg/kg/day ( |
Suppression the inflammatory activities of neutrophils | ||
Acute promyelocytic leukemia | Triptolide | HL-60 cell implanted xenograft in female NOD/SCID mice | 2 or 4 mg/kg ( |
Activatation of mitogen-activated protein kinase kinase-3/p38 signaling pathway | |
Celastrol | HL-60 cell implanted xenograft in nude mice | 2 mg/kg/day ( |
Mitochondrial-initiated apoptosis | ||
Colitis | Triptolide | IL-10-/- mice | 0.07 mg/kg/other day ( |
Suppression of IL-6/STAT3/SOCS3 signaling pathway | |
Celastrol | IL-10-/- mice | 2 mg/kg ( |
Induction of autophage | ||
Celastrol | DSS-induced colitis in C57BL/6J mice | 1 mg/kg ( |
Apoptotic cell death | ||
Celastrol | Caspase 1-/- mice | 1 mg/kg ( |
Inhibiting activation of NLRP3 inflammasommes | ||
Hepatocellular carcinoma | Triptolide | Huh-7 xenograft in nude mice | Minnelide (prodrug of triptolide) 0.21 mg/kg ( |
Inhibiting NF-κB activity | |
Celastrol | DEN-induced HCC in rat | 2, 4, and 8 mg/kg/day ( |
Induction of apoptotic cell death | ||
Gastric cancer | Triptolide | SC-M1 cell xenograft in SCID mice | 0.4 mg/kg ( |
Induction of apoptotic cell death | |
Celastrol | AGS cell xenograft in mice | 1–2 mg/kg/day ( |
Induction of apoptotic cell death | ||
Osteosarcoma | Triptolide | SAOS2 or U2OS cell xenograft in nude mice | 150 nM for 1 to 5 weeks | Induction of apoptotic cell death | |
Celastrol | HOS cell xenograft in nude mice | 1–2 mg/kg/day ( |
Apoptotic cell death | ||
Melanoma | Triptolide | B16-F10 cell xenograft in C57BL/6J mice | 0.15–0.3 mg/kg daily ( |
Regulation of inflammatory T cell number and expression of pro-inflammatory cytokines | |
Celastrol | B16 cell xenograft in C57BL/6J mice | 1–3 mg/kg ( |
Inhibition the PI3K/Akt/mTOR signaling pathway | ||
Pancreatic cancer | Triptolide | SW1990 cell xenograft in BALB/c/nu/nu | 0.2–0.4 mg/kg ( |
Supression of HIF-1α through c-MYC-dependent mechanism | |
Celastrol | PANC-1 cell xenograft in nu/nu athymic female mice | 3 mg/kg ( |
Disturbing HSP90-CDC37 interaction | ||
Mesothelioma | Triptolide | H2373 or H513 cell xenograft in BALB/c/nu mice | 0.42 mg/kg (prodrug of Triptolide, |
Suppression of HSP70 expression | |
Colon cancer | Triptolide | Genotoxic colonic carcinogen- and DSS- induced model in male Crj: CD-1 (ICR) mice | 0.1–1 mg/kg ( |
Reducing inflammation, restrict tumor formation and growth | |
Celastrol | Azoxymethane (AOM) and DSS induced colon cancer in C57BL/6J mice | 2 mg/kg/day by gavage for 14 weeks | Suppressing inflammatory response and epithelial–mesenchymal transition | ||
Lung cancer | Triptolide | Orthotopic lung cancer model in nude rats | 400 μg/kg intranasal instillation for 8 weeks | Targeting the HA-CD44/RHAMM signaling axis | |
Celastrol | A549 or H1975 cell xenograft in Balb/c nude mice | 1 or 3 mg/kg/days, or 5 mg/kg, twice/week ( |
Inhibiting CIP2A-Akt pathway | ||
Neuroinflammation | Triptolide | Middle cerebral artery occlusion in male SD rats | 0.2 mg/kg ( |
Inhibition of NF-κB activity | |
Celastrol | Optic nerve crush (ONC) in adult Brown Norway rats | 1–5 mg/kg ( |
Activation of TNF-α-mediated cell death | ||
Diabetes | Triptolide | High-fat and high-sucrose diet-induced diabetes in Wistar rats | 100 μg/kg ( |
Inhibiting inflammation and macrophage infiltration | |
Celastrol | High energy diet and streptozotocin-induced diabetes in male SD rats | 1–6 mg/kg ( |
Anti-oxidant activity | ||
Obesity | Triptolide | Ob/Ob diabetic mice with diabetic nephropathy | 25 and 50 μg/kg day for up to 12 weeks | Attenuating albuminuria and renal lesion accompanied with dyslipidaemia and obesity | |
Celastrol | High fat diet-induced obesity in C57BL/6J mice | 1–3 mg/kg ( |
Increasing sensitivity to leptin through activtion transcription of HSF1-PGC1α | ||
Celastrol | Nur77-/- mice injected with LPS+GalN | 0.2 or 0.5 mg/kg ( |
Promoting nuclear receptor 77 translocation from nucleus to mitochondria | ||
Celastrol | Ob/Ob mice | 100 μg/kg ( |
Increasing leptin sensitivity | ||
Renal damage | Triptolide | Renal ischemia in SD rats | 4.17 μmol/day ( |
Inhibiting proinflammatory cytokines and chemotactic cytokines expression | |
Celastrol | Renal ischemia in rat | 4–6 mg/kg ( |
Inhibiting NF-κB activation and inflammation | ||
Cardiovascular disease | Triptolide | Ischemia–reperfusion surgery in Wistar rats | 25, 50, and 100 μg/kg 1 h before surgery | Activation of nuclear factor 2/heme oxygenase 1 signaling pathway | |
Celastrol | High-fat/high-cholesterol diet model in apoE-/- mice | 1–2 mg/kg ( |
Inhibiting lectin-like oxidized low density lipprotein | ||
Lung inflammation | Celastrol | Intranasal administration of LPS in male Babl/c mice | 1–50 μg/kg ( |
Inhibiting NF-κB signaling pathway | |
Celastrol | NB4 cells-model of differential syndrome in male NOD/SCID mice | 300 μg/ml ( |
Reducing cytokimes, chemokines, and adhesive molecule expression |
Triptolide, a diterpenoid triepoxide, was first isolated and characterized from TWHF in
Triptolide exhibits anti-inflammation activity in T helper cell-mediated immunity especially against RA and inflammatory bowel diseases. It primarily attenuates inflammatory response in RA by inhibiting NF-κB, NF-κB/TNF-α/vascular cell adhesion molecule-1, and TGF-β1/α-smooth muscle/vimentin signaling pathways induced by TNFs and TLR4 (
Triptolide suppresses abnormally activated innate immune response and attenuates LPS-induced acute lung injury by decreasing leukocyte numbers, myeloperoxidase activity, and secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 (
Triptolide suppresses the proliferation and promotes apoptotic cell death in various cancers, especially hard-to-treat types, including prostate and pancreatic cancers. Prostate and pancreatic cancers are the third and fourth leading causes of cancer death in western countries, respectively (
The generally recognized molecular target of triptolide is the XBP1 subunit of transcription factor TFIIH (
Developing MDR is one of the biggest challenges for cancer therapy (
Celastrol was first reported to inhibit HSP90 by promoting the nuclear translocation of HSF1, a transcription factor regulating HSP genes by binding to the heat shock elements in yeast and mammalian cells (
Classical HSP90 inhibitors suppress the ATPase activity of HSP90 (
HSP90 activity can be modulated through celastrol treatment. Celastrol restores the disrupted association between HSP90 and its co-chaperone CDC37/HSP90-HSP70 complex, and thus reduces HSP90-mediated degradation of glucocerebrosidase (GCase) (
Celastrol effectively inhibits the growth of melanoma xenograft in mouse by triggering ROS-mediated caspase-dependent and caspase-independent apoptotic cell death, and inactivating the PI3K/AKT signaling pathway with the dosage of 1 mg/kg (
Celastrol treatment initiates programmed cell death by activating glycogen synthase kinase-3β (
Treatment with celastrol inhibits the proliferation, migration, and invasion of chondrosarcomas cells by suppressing the inhibitor of the protein phosphatase 2A-Akt signaling pathway
Treatment with celastrol reduces inflammation in several disease models independent of HSP90. Celastrol significantly suppresses inflammation by reducing the secretion of IL-1β and IL-18, and inactivating the NLRP3 inflammasomes and caspase-1 in LPS/ATP-primed macrophage cells (
Metabolic diseases are often associated with over-activated inflammatory response, for example obesity and diabetes (
Despite the various activities offered, clinical application of triptolide and celastrol remains limited due to their narrow therapeutic window and poor solubility (
Lowering the dosage used of TWHF compounds by combining them with agent(s) effectively reduces their cytotoxicity and related adverse effects. Combination treatment offer new opportunities for the translational development of triptolide and celastrol. Active components from the same herb can synergize with other compounds isolated from the same herb (
Triptolide has been used for the reduction of resistance against chemotherapeutic agents. Low doses of triptolide reverses resistance to cytarabine and doxorubicin in acute lymphoblastic leukemia cell line NALM-6/R and primary cells isolated from patients with relapsed or refractory acute lymphoblastic leukemia in the mouse xenograft model (
The combined treatment of celastrol and histone deacetylases inhibitor suberoylanilide hydroxamic acid simultaneously activate the NF-κB and E-cadherin signaling pathway, thus substantially inhibit growth of human cancer cells
Nanoparticle is used as drug delivery system to improve therapeutic efficacy by increasing solubility and organ targeting through electrostatic interactions or receptor and/or membrane binding (
Follicle-stimulating hormone (FSH)-β-peptide modified nanoparticle is used to increase water solubility and reduce cytotoxicity of triptolide in ovarian cancer mouse model (
PEGylated distearoyl phosphatidylcholine liposomes packed with celastrol exhibits higher efficiency in inducing apoptotic cell death in prostate cancer cells, compared with celastrol dissolved in dimethyl sulfoxide (
Several water-soluble analogs of triptolide and celastrol were synthesized and evaluated in laboratory animal models and clinical trials. PG490-88, as a water-soluble succinate salt analog of triptolide, more specifically and effectively blocks pulmonary fibrosis in intratracheal bleomycin mouse model than triptolide (
(5
Minnelide, a phosphonooxymethytriptolide disodium salt, was synthesized by reacting triptolide with acetic anhydride in dimethyl sulfoxide at room temperature for 5 days (
Few C6-indole modified water soluble analogs of celastrol were synthesized. NST001A, a sodium salt of celastrol, inhibits the growth of human colon cancer cell-Colo 205 colon cells
The structural-activity-relationship of major compounds isolated from TWHF against key signaling pathways regulating inflammation have been studied by many groups, aiming to evaluate SAR for the future modifications of TWHF compounds.
The difference in the Michael addition and ring-opening reactions of celastrol, pristimerin, and triptolide may have led to the huge difference among the biological activities of these TWHF compounds. TWHF compounds with the electrophilic structure, including triptolide, celastrol, and pristimerin exhibit similar inhibitory activities against NF-κB, STAT3, and SMAD2/3 signaling pathways (
Activities of major compounds isolated from THWF on different signaling pathways.
Nature product | Activity (EC50a, detection method) | Cell type and viability at EC50 (detection method) | Reference |
---|---|---|---|
Triptolide | Inhibit TRAIL-induced NF-κB at 20 ng/ml (reporter assay) | Lung cancer A549 and NCI-H1299 cell lines, 75–90% (MTT assay) | |
Triptolide | Inhibit IL-6-stimulated STAT3 at 30 nM (reporter assay) | Colon cancer cell line SW480 cells, 10% (MTT assay) | |
Triptolide | Inhibit TGF-β1-activated SMAD2/3 at 10 nM (Western blot analysis) | Airway smooth muscle cells, 70% (MTT assay) | |
Celastrol | Inhibit TGF-β1-stimulated NF-κB at 1000 nM (Western blot analysis) | Squamous cell carcinoma 228 cell, 90% (MTT assay) | |
Celastrol | Inhibit TNF-α-stimulated NF-κB at 3000 nM (reporter assay) | Human embryonic kidney subclone A293 cells, 80% (MTT assay) | |
Celastrol | Inhibit IL-6-stimulated STAT3 at 1000 nM (Western blot analysis) | Multiple myeloma U266 cells, 90% (MTT assay) | |
Pristimerin | Inhibit NF-κB p65/DNA binding activity at 300–400 nM (ELISA assay) | BXPC-3, PNCA-1, and AsPC-1 pancreatic cancer cells, 50% (cell counting) | |
Pristimerin | Inhibit NF-κB p65 protein expression at 600 nM (Western blot analysis) | PNCA-1 cells, 25% (MTS assay) | |
Pristimerin | Inhibit LPS-stimulated NF-κB activation through TLR4 at 500 nM (p65/DNA binding assay) | Cellosaurus BV2 cells, 100% (MTT assay) |
Inspired by the epoxide’s effect on protein proposed by
Chemical structures of compounds isolated from
On the basis of the pharmacological activities of compounds isolated from THWF, especially triptolide and celastrol, we conclude that the systemic evaluation of the
S-RC, YtW, and YW mainly drafted the work critical for important intellectual content; YD, JZ, and LL finished the SAR discussion; all authors approved the version to be published.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
AMP-activated protein kinase
adenosine triphosphate
bone morphogenetic protein
cell division cycle
cyclin dependent kinase
cytochrome protein
diethylnitrosamine
endoplasmic reticulum
glucocerebrosidase
hepatocellular carcinoma
heat shock factor
heat shock protein
interferon
interleukin
lipopolysaccharide
multi-drug resistance
mammalian target of rapamycin
nuclear factor
NLR family pyrin domain containing 3
non-small cell lung carcinoma
rheumatoid arthritis
reactive oxygen species
retinoid X receptor-α
inositol polyphosphate-5-phosphatease
signal transducer and activator of transcription
transforming growth factor
toll-like receptor
tumor necrosis factor
T regulatory
X box binding protein 1