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Open AccessArticle

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

1
Department of Dermatology, Venereology and Allergology, Goethe-University, 60438 Frankfurt am Main, Germany
2
Department of Radiation Oncology, UniversitätsSpital, 8091 Zürich, Switzerland
*
Author to whom correspondence should be addressed.
Cells 2019, 8(11), 1329; https://doi.org/10.3390/cells8111329
Received: 9 August 2019 / Revised: 18 October 2019 / Accepted: 25 October 2019 / Published: 28 October 2019
(This article belongs to the Section Cell Signaling and Regulated Cell Death)
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 anti-tumorigenic, 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. View Full-Text
Keywords: dimethylfumarate; colorectal carcinoma; p21; cell cycle arrest; cyclin D1; p62; LC3 I/II; caspase-8; autophagy dimethylfumarate; colorectal carcinoma; p21; cell cycle arrest; cyclin D1; p62; LC3 I/II; caspase-8; autophagy
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Kaluzki, I.; Hailemariam-Jahn, T.; Doll, M.; Kaufmann, R.; Balermpas, P.; Zöller, N.; Kippenberger, S.; Meissner, M. Dimethylfumarate Inhibits Colorectal Carcinoma Cell Proliferation: Evidence for Cell Cycle Arrest, Apoptosis and Autophagy. Cells 2019, 8, 1329.

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