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.
Highlights
The transcription factor MYC plays a key role in the regulation of cell growth, differentiation and apoptosis [1]
Diclofenac inhibits melanoma cell proliferation in vitro The addition of diclofenac, which is a member of the arylacetic acid group of non-steroidal anti-inflammatory drugs (NSAIDs), at clinically relevant concentrations led to significant effects on several tumor cell lines starting at concentrations as low as 0.1 mM
The proliferation of the human melanoma cell line MelIm was inhibited significantly (p,0.001) at 0.4 mM diclofenac (Fig. 1A) and reduction in proliferation was comparable to that of the standard chemotherapeutic drug gemcitabine (Fig. S1A In contrast, aspirin (ASA), a typical NSAID exerted no impact on proliferation indicating a COX-independent effect of diclofenac (Fig. 1B)
Summary
The transcription factor MYC plays a key role in the regulation of cell growth, differentiation and apoptosis [1]. Lactate transport can be blocked by pharmacological means as non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the transport of lactate in a human trophoblast cell line and chinese hamster ovary (CHO) cells [19;20]. This effect of NSAIDs has never been addressed with regard to inhibition of tumor growth, several epidemiological studies report that the use of NSAIDs is linked to a lower risk of inflammation-associated tumors like colon, oesophagus and breast cancer [21;22]. Anti-tumor effects of NSAIDs have been attributed mainly to the inhibition of cyclooxygenase (COX1/2) and their anti-inflammatory effects, albeit COX-
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