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.

Stromal cell–mediated glycolytic switch in CLL cells involves Notch-c-Myc signaling

“…19 Despite the demonstrated tumor-promoting effects ( Figure 1A), shifts of cellular energetics away from oxidative phosphorylation could increase the CLL cells' reliance on glucose and thereby render them more susceptible toward perturbations within their glycolytic framework. 20 In fact, treating CLL cells with 2-deoxy-D-glucose and diclofenac 21 that both target glucose metabolism revealed an increased sensitivity upon stromal contact ( Figure 1K).…”

Adipose tissue dysfunction and its effects on tumor metabolism

“…Interestingly, a study using, diclofenac, a nonsteroidal anti-inflammatory drug, showed suppression of c-MYC. This down-regulation of c-MYC that resulted in significantly reduced levels of GLUT1, LDH-α, MCT1 and coincident decrease in glucose import and lactate secretion by human melanoma cells in vitro, validating the importance of targeting this transcription factor for anti-cancer therapy [327–329]. The most current, ongoing clinical trials targeting various aspects of metabolism in cancer cells are listed in Table 1.…”

Effect of nonsteroidal ant-inflammatory drugs on carcinogenesis

“…На первичных культурах рака яичников челове-ка in vitro эти НПВС вызывали арест клеточного цикла и апоптоз опухолевых клеток [15]. Диклофенак тормозил рост меланомы in vivo у мышей и клеточной линии мела-номы in vitro [16].…”

“…НПВС in vitro блокируют его, что приводит к снижению экс-прессии генов-мишеней β-катенина-циклина D 1 , cМyc и Axin2 и стимуляции NF-kB сигнального пути, что было показано на культуре клеток как колоректального рака [17], так и глиобластомы [13], и меланомы [16].…”

“…Кроме того, в экспериментальных исследованиях in vivo и in vitro на модели культуры и перевивной линии меланомы было установлено, что НПВС (например, ди-клофенак) изменяет метаболизм глюкозы в клетках, сни-жая экспрессию ассоциированных с ним генов LDH-A, GLUT-1 и MCT-1. Авторы полагают, что снижение про-лиферации опухолевых клеток под действием диклофе-нака идет по двум независимым механизмам -через снижение экспрессии сMyс и вследствие накопления в клетках лактата [16].…”