Gottfried, Eva and Lang, Sven A. and Renner, Kathrin and Bosserhoff, Anja and Gronwald, Wolfram and Rehli, Michael and Einhell, Sabine and Gedig, Isabel and Singer, Katrin and Seilbeck, Anton and Mackensen, Andreas and Grauer, Oliver and Hau, Peter and Dettmer, Katja and Andreesen, Reinhard and Oefner, Peter J. and Kreutz, Marina (2013) New Aspects of an Old Drug - Diclofenac Targets MYC and Glucose Metabolism in Tumor Cells. PLOS ONE, 8 (7): e66987. ISSN 1932-6203,
Full text not available from this repository. (Request a copy)Abstract
Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects. Up to now these effects were mainly attributed to its classical role as COX-inhibitor. Here we show novel COX-independent effects of diclofenac. Diclofenac significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanoma, leukemia, and carcinoma cell line proliferation in vitro and reduced melanoma growth in vivo. In contrast, the non-selective COX inhibitor aspirin and the COX-2 specific inhibitor NS-398 had no effect on MYC expression and glucose metabolism. Diclofenac significantly decreased glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 1 (MCT1) gene expression in line with a decrease in glucose uptake and lactate secretion. A significant intracellular accumulation of lactate by diclofenac preceded the observed effect on gene expression, suggesting a direct inhibitory effect of diclofenac on lactate efflux. While intracellular lactate accumulation impairs cellular proliferation and gene expression, it does not inhibit MYC expression as evidenced by the lack of MYC regulation by the MCT inhibitor alpha-cyano-4-hydroxycinnamic acid. Finally, in a cell line with a tetracycline-regulated c-MYC gene, diclofenac decreased proliferation both in the presence and absence of c-MYC. Thus, diclofenac targets tumor cell proliferation via two mechanisms, that is inhibition of MYC and lactate transport. Based on these results, diclofenac holds potential as a clinically applicable MYC and glycolysis inhibitor supporting established tumor therapies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NONSTEROIDAL ANTIINFLAMMATORY DRUGS; COLON-CANCER CELLS; C-MYC; IN-VIVO; MONOCARBOXYLATE TRANSPORTERS; MALIGNANT-MELANOMA; INDUCED APOPTOSIS; INDUCE APOPTOSIS; SALICYLIC-ACID; GROWTH; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Lehrstuhl für Neurologie Medicine > Lehrstuhl für Pathologie Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 Apr 2020 09:31 |
| Last Modified: | 06 Apr 2020 09:31 |
| URI: | https://pred.uni-regensburg.de/id/eprint/16370 |
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