Celastrol Ameliorates Ulcerative Colitis-Related Colorectal Cancer in Mice via Suppressing Inflammatory Responses and Epithelial-Mesenchymal Transition

Abstract

Celastrol, also named as tripterine, is a pharmacologically active ingredient extracted from the root of traditional Chinese herb Tripterygium wilfordii Hook F with potent anti-inflammatory and anti-tumor activities. In the present study, we investigated the effects of celastrol on ulcerative colitis-related colorectal cancer (UC-CRC) as well as CRC in vivo and in vitro and explored its underlying mechanisms. UC-CRC model was induced in C57BL/6 mice by administration of azoxymethane (AOM) and dextran sodium sulfate (DSS). Colonic tumor xenograft models were developed in BALB/c-nu mice by subcutaneous injection with HCT116 and HT-29 cells. Intragastric administration of celastrol (2 mg/kg/d) for 14 weeks significantly increased the survival ratio and reduced the multiplicity of colonic neoplasms compared with AOM/DSS model mice. Mechanically, celastrol treatment significantly prevented AOM/DSS-induced up-regulation of expression levels of oncologic markers including mutated p53 and phospho-p53, β-catenin and proliferating cell nuclear antigen (PCNA). In addition, treatment with celastrol inhibited inflammatory responses, as indicated by the decrease of serum tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, down-regulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), and inactivation of nuclear factor κB (NF-κB). Moreover, celastrol obviously suppressed epithelial-mesenchymal transition (EMT) through up-regulating E-cadherin and down-regulating N-cadherin, Vimentin and Snail. Additionally, we also demonstrated that celastrol inhibited human CRC cell proliferation and attenuated colonic xenograft tumor growth via reversing EMT. Taken together, celastrol could effectively ameliorate UC-CRC by suppressing inflammatory responses and EMT, suggesting a potential drug candidate for UC-CRC therapy.

Intestinal Autophagy and Its Pharmacological Control in Inflammatory Bowel Disease

“…It is a kind of triterpenoid extracted from the root of a traditional Chinese medicine called Tripterygium wilfordii . It was reported that celastrol could inhibit the development of IBD or colitis through several pathways, including: (1) regulating the oxidative stress and reducing lipid peroxide; (2) inhibiting the activation of the NLRP3 inflammasome; (3) increasing the levels of anti-inflammatory cytokines like IL-10; (4) enhancing the stability of intestinal epithelial barrier (152); (5) inhibiting the receptor interacting-protein 3/mixed lineage kinase domain-like protein-mediated programed necrosis pathway (153); and (6) inhibiting the production of NF-κB and its related inflammatory cytokines (154). Furthermore, it has been proven that celastrol can enhance the level of autophagy through the inhibition of the PI3K/Akt/mTOR signaling pathway in the colon tissue, and meanwhile reduce the production of several pro-inflammatory cytokines thus attenuating the inflammatory reaction in colon in IL-10-deficient mice (155).…”

Celastrol inhibits glucocorticoid‑induced osteoporosis in rat via the PI3K/AKT and Wnt signaling pathways

“…The present study demonstrated that treatment with Celastrol significantly promoted Wnt and β-catenin protein expression levels in GIOP mice. Lin et al (12) previously reported that Celastrol ameliorates ulcerative colitis-associated colorectal cancer through β-catenin expression. The findings of the present study are consistent with previous finding (12) regarding the role of Celastrol as an effective activator of the Wnt/β-catenin pathway in GIOP mice and has a protective effect.…”

“…1) has anti-oxidative and anti-inflammatory properties, inhibits atherosclerosis by lipoprotein oxidative modification and prevents against inflammation (11). Previous studies have revealed that Celastrol has anti-inflammatory, anti-bacterial, anti-viral, anti-fertility and insect-resistance functions, and has been used for the treatment of rheumatism, rheumatoid arthritis, blood diseases, skin diseases and as an agricultural insecticide (11,12). In the present study, bioinformatics analysis was used to investigate the effects of Celastrol on glucocorticoid-induced osteoporosis (GIOP) and the potential underlying molecular mechanisms.…”

Celastrol and its Potential Health Benefits

“…[12][13][14] Ayrıca; celastrolün hücre proliferasyonunu, apoptozu, proteazom aktivitesini,anjiyogenezi, ısı şok protein yanıtını ve adaptif immün yanıtı düzenlediği de bildirilmiştir. [15][16][17][18][19][20][21]…”