Shenling Baizhu San supresses colitis associated colorectal cancer through inhibition of epithelial-mesenchymal transition and myeloid-derived suppressor infiltration

Lin, Xiaochang; Xu, Wanhai; Shao, Meng; Fan, Qian; Wen, Gen; Li, Changke; Jing, Linyuan; Sun, Xuegang

doi:10.1186/s12906-015-0649-9

Cited by 34 publications

(24 citation statements)

References 35 publications

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“…Moreover, β-catenin and PCNA, as two important oncogenic transcription factors, have also been reported to play crucial roles during UC-associated colon carcinogenesis ( Cappello et al, 2003 ; Nelson and Nusse, 2004 ; Clevers, 2006 ; Georgescu et al, 2007 ). Our results clearly demonstrated that the expression levels of β-catenin and PCNA in colonic tissues were significantly up-regulated by AOM/DSS, which was in line with previous studies ( Lin et al, 2014 , 2015 ). Nevertheless, administration of celastrol significantly prevented up-regulation of these neoplastic markers.…”

Section: Discussionsupporting

confidence: 93%

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

et al. 2016

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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.

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Section: Discussionsupporting

confidence: 93%

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

et al. 2016

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“…Our results disclosed that CRC patients with low E-cadherin levels had a poorer 5-year OS rate, while loss of Vimentin could lead to an improved clinical outcome in CRC. All these results were consistent with the predictions of previous studies, which supported the role of EMT in CRC progression, particularly the changes of epithelial or mesenchymal traits during EMT [24,25]. CMTM proteins contain a MARVEL domain, which is involved in many essential cellular processes including tumor suppression.…”

Section: Discussionsupporting

confidence: 92%

The prognostic significance of CMTM3 in colorectal cancer and association with the phenomenon of EMT

Chen¹,

Ren²,

Zhao³

et al. 2018

Oncotarget

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CKLF-like MARVEL transmembrane domain containing 3 (CMTM3), which is located at the critical tumor suppressor locus 16q22.1, has been proposed as a putative tumor suppressor gene in multiple types of malignancies. However, its role in colorectal cancer (CRC) has not been clearly defined. In this study, the potential relationships between CMTM3 and epithelial-mesenchymal transition (EMT)-related proteins were firstly analyzed in the clinical tissues. Our data demonstrated that CMTM3 presented a relatively negative staining in 130 CRC tissues, compared to their corresponding normal-appearing tissues (NATs) (P < 0.05). The reduction of CMTM3 protein was associated with the advanced depth of invasion, distant metastasis and tumor stage (P < 0.05). CRC patients with low CMTM3 levels had a poorer 5-year overall survival (OS) rate (P = 0.035), and the decreased level of CMTM3 could be served as an independent and significant prognostic factor of CRC patients (P = 0.013). Meanwhile, a significant positive relationship between CMTM-3 and E-cadherin was found (r = 0.253, P = 0.004), whereas CMTM3 negatively correlated with Vimentin (r = −0.506 P = 0.000). To better understand the tumor suppressing effect of CMTM3 in CRC progression through an EMT-dependent mechanism, we found that up-regulation of CMTM3 significantly suppressed the abilities of cell proliferation, migration and invasion in CRC cells in vitro (P < 0.05). The results of western blot analysis also disclosed that CMTM3 influenced the expressions of EMT-related proteins (E-cadherin, N-cadherin and Vimentin) (P < 0.05). These results suggested that CMTM3 might be involved in the EMT process of CRC, and could be considered as a potentially important molecular treatment strategy for early stage CRC patients.

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“…Colorectal cancer, accompanied by intestinal microflora disorders, inflammation, metabolic dysfunction symptoms, and invasion of pathogens, remains the third most commonly diagnosed cancer and the fourth leading cause of cancer-related mortality worldwide [ 1 , 2 , 3 ]. Besides surgery, chemotherapy appears to be a primary therapeutic strategy for colorectal cancer largely due to the fact that most patients present at diagnosis with unresectable or metastatic disease [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Hepatoprotective Effect of Carboxymethyl Pachyman in Fluorouracil-Treated CT26-Bearing Mice

et al. 2017

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5-Fluorouracil (5-FU) is the chemotherapeutic agent of first choice for the treatment ofcolorectal cancer, however, treatment-related liver toxicity remains a major concern. Thereby, it is desirable to search for novel therapeutic approaches that can effectively enhance curative effects and reduce the toxic side effects of 5-FU. Carboxymethyl Pachyman (CMP) exhibits strong antitumor properties, but the antitumor and hepatoprotective effects of CMP and the molecular mechanisms behind these activities, are however poorly explored. Thereby, the purpose of the present study was to evaluate the hepatoprotective effect of CMP in 5-FU-treated CT26-bearing mice, and further explore the underlying mechanism(s) of action. Initially, a CT26 colon carcinoma xenograft mice model was established. The immune organ indexes, blood indicators, liver tissue injury, and indicators associated with inflammation, antioxidant and apoptosis were then measured. Our results showed that CMP administration increased the tumor inhibitory rates of 5-FU and, meanwhile, it reversed reduction of peripheral white blood cells (WBC) and bone marrow nucleated cells (BMNC), increase of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and decrease of superoxide dismutase (SOD), catalase (CAT), GSH-Px and glutathione(GSH) induced by 5-FU. Moreover, CMP in combination with 5-FU alleviated severe liver injury induced by 5-FU via reducing the levels of ROS, IL-1β, and IL-6, decreasing expression of p-IκB-α, NF-κB, p-NF-κB, pp38 and Bax, and elevating levels of Nrf2, GCL, HO-1 and Bcl-2. Collectively, these outcomes suggested that CMP effectively enhanced the curative effects of 5-FU and simultaneously reduced the liver injuries induced by 5-FU in CT26-bearing mice, and the mechanism may be associated with regulation of NF-κB, Nrf2-ARE and MAPK/P38/JNK pathways.

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Shenling Baizhu San supresses colitis associated colorectal cancer through inhibition of epithelial-mesenchymal transition and myeloid-derived suppressor infiltration

Cited by 34 publications

References 35 publications

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

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

The prognostic significance of CMTM3 in colorectal cancer and association with the phenomenon of EMT

Hepatoprotective Effect of Carboxymethyl Pachyman in Fluorouracil-Treated CT26-Bearing Mice

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