6-mercaptopurine promotes energetic failure in proliferating T cells

Abstract

The anticancer drug 6-mercaptopurine (6-MP) inhibits de novo purine synthesis and acts as an antiproliferative agent by interfering with protein, DNA and RNA synthesis and promoting apoptosis. Metabolic reprogramming is crucial for tumor progression to foster cancer cells growth and proliferation, and is regulated by mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) as well as the oncogenes Myc and hypoxia inducible factor 1α (HIF-1α). We hypothesized that 6-MP impacts metabolic remodeling through its action on nucleotide synthesis. The aim of our study is to provide a comprehensive characterization of the metabolic changes induced by 6-MP in leukemic T cells. Our results indicate that exposition to 6-MP rapidly reduces intracellular ATP concentration, leading to the activation of AMPK. In turn, mTOR, an AMPK target, was inhibited, and the expression of HIF-1α and Myc was reduced upon 6-MP incubation. As a consequence of these inhibitions, glucose and glutamine fluxes were strongly decreased. Notably, no difference was observed on glucose uptake upon exposition to 6-MP. In conclusion, our findings provide new insights into how 6-MP profoundly impacts cellular energetic metabolism by reducing ATP production and decreasing glycolytic and glutaminolytic fluxes, and how 6-MP modifies human leukemic T cells metabolism with potential antiproliferative effects.

mTOR Regulation of Metabolism in Hematologic Malignancies

“…In this context, mTOR seems therefore to drive cells toward a more sustained metabolism, with higher fluxes of glycolysis followed by an OXPHOS upregulation. An indirect evidence has in fact been reported by Fernández-Ramos et al, who observed that 6-mercaptopurine inhibits mTOR through AMPK activation, consequently reducing glucose and glutamine consumption by T leukemia cells [97]. In Table 2, the metabolic effects of mTOR inhibition in B-and T-ALL are reported.…”

The immunosuppressant drug azathioprine restrains adipogenesis of muscle Fibro/Adipogenic Progenitors from dystrophic mice by affecting AKT signaling

“…Tested in a randomized trial in DMD patients as an alternative immunosuppressant, AZA did not exert any physical benefit when compared to prednisone 29 , although muscle biopsies showed comparable immunohistological ameliorations 30 . While the primary mechanism underlying AZA pharmacological activity can be imputed to its interference with DNA synthesis 31 , 32 , alternative biological processes have been implicated in the drug mechanism of action 19 , 20 , 33 – 37 .…”

Limited Impact of 6-Mercaptopurine on Inflammation-Induced Chemokines Expression Profile in Primary Cultures of Enteric Nervous System

“…6-MP has been widely used for the clinical treatment of IBD [23] and recent studies have given evidences for direct anti-inflammatory properties of 6-MP [25,28,48]. In particular, 6-MP was shown to inhibit the induced expression of Fig.…”

“…Recent evidences have been provided in support of direct anti-inflammatory functions of 6-MP, occurring independently of its cytostatic activity. Indeed, 6-MP has been shown to promote T-cell cycle arrest and apoptosis in the Jurkat human T lymphocyte cell line [25]. Furthermore, 6-MP regulates the transcriptional activities of the orphan nuclear receptors NR4A1-3, which are involved in the regulation of inflammatory reactions and neoplasia [26,27].…”