title: New aspects of an old drug--diclofenac targets MYC and glucose metabolism in tumor cells.
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 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.
authors.affiliation: Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Gottfried
authors.forename: Sven A
authors.initials: SA
authors.lastname: Lang
authors.forename: Kathrin
authors.initials: K
authors.lastname: Renner
authors.forename: Anja
authors.initials: A
authors.lastname: Bosserhoff
authors.forename: Wolfram
authors.initials: W
authors.lastname: Gronwald
authors.forename: Michael
authors.initials: M
authors.lastname: Rehli
authors.forename: Sabine
authors.initials: S
authors.lastname: Einhell
authors.forename: Isabel
authors.initials: I
authors.lastname: Gedig
authors.forename: Katrin
authors.initials: K
authors.lastname: Singer
authors.forename: Anton
authors.initials: A
authors.lastname: Seilbeck
authors.forename: Andreas
authors.initials: A
authors.lastname: Mackensen
authors.forename: Oliver
authors.initials: O
authors.lastname: Grauer
authors.forename: Peter
authors.initials: P
authors.lastname: Hau
authors.forename: Katja
authors.initials: K
authors.lastname: Dettmer
authors.forename: Reinhard
authors.initials: R
authors.lastname: Andreesen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.forename: Marina
authors.initials: M
authors.lastname: Kreutz
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004008:Diclofenac / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D007938:Leukemia / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016271:Proto-Oncogene Proteins c-myc; D004008:Diclofenac; D019344:Lactic Acid; D005947:Glucose