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

• Published in: Cells (Basel, Switzerland) Switzerland), 2019-10, Vol.8 (11), p.1329
• Main Authors: Kaluzki, Irina, Hailemariam-Jahn, Tsige, Doll, Monika, Kaufmann, Roland, Balermpas, Panagiotis, Zöller, Nadja, Kippenberger, Stefan, Meissner, Markus
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Bromodeoxyuridine; Caspase; caspase-8; Cell cycle; Cell Cycle - drug effects; cell cycle arrest; Cell Cycle Checkpoints - drug effects; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Chemotherapy; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cytotoxicity; Dimethyl Fumarate - metabolism; Dimethyl Fumarate - pharmacology; dimethylfumarate; G1 phase; Humans; Immunoblotting; Immunofluorescence; lc3 i/ii; Medical prognosis; Melanoma; Melanoma - metabolism; Melanoma, Cutaneous Malignant; Oxaliplatin; p21; p62; Phagocytosis; Radiation; Skin Neoplasms - metabolism; Tumor cell lines
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells8111329

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.