New aspects of an old drug--diclofenac targets MYC and glucose metabolism in tumor cells.
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 modulate...
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2013
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oai:doaj.org-article:64919e4e9d61407e8bc01ae34269ec632021-11-18T07:38:15ZNew aspects of an old drug--diclofenac targets MYC and glucose metabolism in tumor cells.1932-620310.1371/journal.pone.0066987https://doaj.org/article/64919e4e9d61407e8bc01ae34269ec632013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23874405/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Non-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 α-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.Eva GottfriedSven A LangKathrin RennerAnja BosserhoffWolfram GronwaldMichael RehliSabine EinhellIsabel GedigKatrin SingerAnton SeilbeckAndreas MackensenOliver GrauerPeter HauKatja DettmerReinhard AndreesenPeter J OefnerMarina KreutzPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 7, p e66987 (2013) |
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| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Eva Gottfried Sven A Lang Kathrin Renner Anja Bosserhoff Wolfram Gronwald Michael Rehli Sabine Einhell Isabel Gedig Katrin Singer Anton Seilbeck Andreas Mackensen Oliver Grauer Peter Hau Katja Dettmer Reinhard Andreesen Peter J Oefner Marina Kreutz New aspects of an old drug--diclofenac targets MYC and glucose metabolism in tumor cells. |
| description |
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 α-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. |
| format |
article |
| author |
Eva Gottfried Sven A Lang Kathrin Renner Anja Bosserhoff Wolfram Gronwald Michael Rehli Sabine Einhell Isabel Gedig Katrin Singer Anton Seilbeck Andreas Mackensen Oliver Grauer Peter Hau Katja Dettmer Reinhard Andreesen Peter J Oefner Marina Kreutz |
| author_facet |
Eva Gottfried Sven A Lang Kathrin Renner Anja Bosserhoff Wolfram Gronwald Michael Rehli Sabine Einhell Isabel Gedig Katrin Singer Anton Seilbeck Andreas Mackensen Oliver Grauer Peter Hau Katja Dettmer Reinhard Andreesen Peter J Oefner Marina Kreutz |
| author_sort |
Eva Gottfried |
| title |
New aspects of an old drug--diclofenac targets MYC and glucose metabolism in tumor cells. |
| title_short |
New aspects of an old drug--diclofenac targets MYC and glucose metabolism in tumor cells. |
| title_full |
New aspects of an old drug--diclofenac targets MYC and glucose metabolism in tumor cells. |
| title_fullStr |
New aspects of an old drug--diclofenac targets MYC and glucose metabolism in tumor cells. |
| title_full_unstemmed |
New aspects of an old drug--diclofenac targets MYC and glucose metabolism in tumor cells. |
| title_sort |
new aspects of an old drug--diclofenac targets myc and glucose metabolism in tumor cells. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/64919e4e9d61407e8bc01ae34269ec63 |
| work_keys_str_mv |
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| _version_ |
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