Dimethylfumarate effectively inhibits lymphangiogenesis via p21 induction and G1 cell cycle arrest

Valesky, Eva Maria; Hrgović, Igor; Doll, Monika; Wang, Xiaofan; Pinter, Andreas; Kleemann, Johannes; Kaufmann, Roland; Kippenberger, Stefan; Meißner, Markus

doi:10.1111/exd.12907

Cited by 15 publications

(11 citation statements)

References 50 publications

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“…The progression of the cell cycle is regulated by a number of negative regulators termed CDK inhibitors, including p21 Cip1 and p27 Kip1 (27). p21 Cip1 is a universal cell cycle inhibitor that binds to cyclin-CDK complexes and proliferating cell nuclear antigen, thereby inducing cell cycle arrest at the G1 phase (28). In addition, the upregulation of p21 Cip1 and p27 Kip1 enhances the formation of complexes with G1-S CDKs and cyclins, thereby, inhibiting their activities (29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

Bergapten induces G1 arrest of non‑small cell lung cancer cells, associated with the p53‑mediated cascade

Chiang

Lin

et al. 2019

Mol Med Report

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The pr incipal subtype of lung cancer, non-small cell lung cancer (NSCLC) is a life-threatening malignancy that causes high mortality rates. Bergapten (5-methoxypsoralen) has been identified to possess anticancer activity against a number of carcinomas. In the present study, the effects of bergapten on NSCLC cells were investigated. The cell viability was determined by MTT assay. Cell cycle distribution was analyzed using flow cytometry. Protein expression and kinase cascade were demonstrated using western blot analysis. The results demonstrated that treatment with bergapten (50 µM for 48 h) inhibited the viability of A549 and NCI-H460 NSCLC cells to 79.1±2.8% and 74.5±3.1%, respectively, compared with the controls. It was identified that bergapten induced G1 phase accumulation in A549 and NCI-H460 cells between ~58 and 75% (P<0.01). In addition, bergapten significantly increased the sub-G1 phase ratio to ~9% (P<0.05) in the two cell types. Further investigation demonstrated that bergapten upregulated the expression of cellular tumor antigen p53 (p53) and its downstream proteins cyclin-dependent kinase inhibitor 1 and cyclin-dependent kinase inhibitor 1B, whereas, it downregulated the expression of cyclin D1 and CDK4. Overall, these results suggested that bergapten may inhibit cell viability and trigger G1 arrest and apoptosis in A549 and NCI-H460 cells, which may be attributed to the activation of p53-mediated cascades. Therefore, bergapten may be beneficial for NSCLC treatment.

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Section: Discussionmentioning

confidence: 99%

Bergapten induces G1 arrest of non‑small cell lung cancer cells, associated with the p53‑mediated cascade

Chiang

Lin

et al. 2019

Mol Med Report

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“…Furthermore, it could be demonstrated that MMF is a metabolite of DMF enhanced CD56 + natural killer cell lysis of tumor cells by degranulation and upregulation of NKp46 and CD107a [9]. In addition, our group could demonstrate that DMF effectively inhibits angiogenesis and lymphangiogenesis in part by downregulation of a vascular endothelial growth factor receptor (VEGFR)-2 [10,11]. All of these results illustrate that DMF seems to have potential antitumorigenic effects.…”

Section: Introductionmentioning

confidence: 95%

“…Various authors demonstrated that DMF suppresses the activation as well as the nuclear translocation of Nuclear factor kappa B (NfkB) and therefore characterize p65 as a central target of DMF [12,13,14]. In addition, p21 and the cell cycle seem to be important targets of DMF [4,10,15].…”

Section: Introductionmentioning

confidence: 99%

Dimethylfumarate Inhibits Colorectal Carcinoma Cell Proliferation: Evidence for Cell Cycle Arrest, Apoptosis and Autophagy

Kaluzki

Hailemariam-Jahn

Doll

et al. 2019

Cells

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Recent studies have proven that Dimethylfumarate (DMF) has a marked anti-proliferative impact on diverse cancer entities e.g., on malignant melanoma. To explore its anti-tumorigenic potential, we examined the effects of DMF on human colon carcinoma cell lines and the underlying mechanisms of action. Human colon cancer cell line HT-29 and human colorectal carcinoma cell line T84 were treated with or without DMF. Effects of DMF on proliferation, cell cycle progression, and apoptosis were analyzed mainly by Bromodeoxyuridine (BrdU)- and Lactatdehydrogenase (LDH)assays, caspase activation, flowcytometry, immunofluorescence, and immunoblotting. In addition, combinational treatments with radiation and chemotherapy were performed. DMF inhibits cell proliferation in both cell lines. It was shown that DMF induces a cell cycle arrest in G0/G1 phase, which is accompanied by upregulation of p21 and downregulation of cyclin D1 and Cyclin dependent kinase (CDK)4. Furthermore, upregulation of autophagy associated proteins suggests that autophagy is involved. In addition, the activation of apoptotic markers provides evidence that apoptosis is involved. Our results show that DMF supports the action of oxaliplatin in a synergetic manner and failed synergy with radiation. We demonstrated that DMF has distinct antitumorigenic, cell dependent effects on colon cancer cells by arresting cell cycle in G0/G1 phase as well as activating both the autophagic and apoptotic pathways and synergizes with chemotherapy.

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“…Because PCNA needs to be ubiquitinated for performing its biological function, these up-regulations of PCNA could not be certainly related to its promoted functions. On the other hand, p21 induces cell cycle arrest at G 1 42 and G 2 M 43 phases by inhibiting the activity of CDKs such as CDK6, CDK2 and cdc2 42 , 44 . In this study, we found that the expressions of cyclin B 3 /cdc2 and cyclin D 1 /CDK6 complexs were decreased in the AFB 1 group during the experiment.…”

Section: Discussionmentioning

confidence: 99%

The molecular mechanism of cell cycle arrest in the Bursa of Fabricius in chick exposed to Aflatoxin B 1

Zuo

et al. 2018

Sci Rep

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Aflatoxin B 1 shows potent hepatotoxic, carcinogenic, genotoxic, immunotoxic potential in humans and many species of animals. The aim of this study was to clarify the underlying mechanism of G 0 G 1 phase and G 2 M phase arrest of cell cycle in the bursa of Fabricius in broilers exposed to dietary AFB 1 . 144 one-day-old healthy Cobb broilers were randomly divided into two groups and fed on control diet and 0.6 mg·Kg Aflatoxin B 1 (AFB 1 ), secondary metabolites generated by the fungi Aspergillus flavus and Aspergillus parasiticus, usually can contaminate agricultural products and threaten food safety 1 . AFB 1 also presents potent hepatotoxic, carcinogenic, genotoxic, immunotoxic potential 2,3 and other adverse effects in many species of animals, including rodents, fish, humans and non-human primates 4 . Immunosuppression is a major effect of AFB 1 , which is characterized by injuries of mucosal immunity, cellular immunity and humoral immunity. These injuries include alteration of organ morphology and immune organ weights, reduction of T or B lymphocytes number, inhibition of lymphocyte activity 5,6 , decrease of antibody production 7

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Dimethylfumarate effectively inhibits lymphangiogenesis via p21 induction and G1 cell cycle arrest

Cited by 15 publications

References 50 publications

Bergapten induces G1 arrest of non‑small cell lung cancer cells, associated with the p53‑mediated cascade

Bergapten induces G1 arrest of non‑small cell lung cancer cells, associated with the p53‑mediated cascade

Dimethylfumarate Inhibits Colorectal Carcinoma Cell Proliferation: Evidence for Cell Cycle Arrest, Apoptosis and Autophagy

The molecular mechanism of cell cycle arrest in the Bursa of Fabricius in chick exposed to Aflatoxin B 1

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