Aspirin and the metabolic hallmark of cancer: novel therapeutic opportunities for colorectal cancer

Abstract

Aspirin is a well-known nonsteroidal anti-inflammatory drug (NSAID) that has a recognized role in cancer prevention as well as evidence to support its use as an adjuvant for cancer treatment. Importantly there has been an increasing number of studies contributing to the mechanistic understanding of aspirins' anti-tumour effects and these studies continue to inform the potential clinical use of aspirin for both the prevention and treatment of cancer. This review focuses on the emerging role of aspirin as a regulator of metabolic reprogramming, an essential "hallmark of cancer" required to support the increased demand for biosynthetic intermediates needed for sustained proliferation. Cancer cells frequently undergo metabolic rewiring driven by oncogenic pathways such as hypoxia-inducible factor (HIF), wingless-related integration site (Wnt), mammalian target of rapamycin (mTOR), and nuclear factor kappa light chain enhancer of activated B cells (NF-κB), which supports the increased proliferative rate as tumours develop and progress. Reviewed here, cellular metabolic reprogramming has been identified as a key mechanism of action of aspirin and include the regulation of key metabolic drivers, the regulation of enzymes involved in glycolysis and glutaminolysis, and altered nutrient utilisation upon aspirin exposure. Importantly, as aspirin treatment exposes metabolic vulnerabilities in tumour cells, there is an opportunity for the use of aspirin in combination with specific metabolic inhibitors in particular, glutaminase (GLS) inhibitors currently in clinical trials such as telaglenastat (CB-839) and IACS-6274 for the treatment of colorectal and potentially other cancers. The increasing evidence that aspirin impacts metabolism in cancer cells suggests that aspirin could provide a simple, relatively safe, and cost-effective way to target this important hallmark of cancer. Excitingly, this review highlights a potential new role for aspirin in improving the efficacy of a new generation of metabolic inhibitors currently undergoing clinical investigation.

Keywords: Aspirin; adjuvant for therapy; anti-tumour; cancer metabolism; cancer prevention; colorectal cancer; metabolic hallmark; nonsteroidal anti-inflammatory drugs.

Figure 1

Oncogenic drivers regulated by aspirin. Aspirin has been shown to inhibit or reduce the activity of key oncogenic drivers, many of which inhibit the “hallmarks of cancer” [41]. This includes Wnt signalling and its downstream effectors, HIF-1α, the PI3K/Akt/mTOR signalling axis, NF-κB signalling, and COX1/2 and its downstream effectors. Aspirin has also been shown to increase the acetylation and stability of p53 leading to cell cycle arrest and apoptosis. Together this demonstrates how aspirin impacts a number of the hallmarks of cancer. The green arrows indicate that aspirin promotes that effect/pathway and the red blunt arrows indicate that aspirin inhibits it. The figure was created with BioRender.com. c-myc: cellular myc; Akt: protein kinase B or Akt

Figure 2

Metabolic reprogramming of tumour cells. In non-malignant cells under aerobic conditions, glucose is utilised as the primary fuel source to generate ATP via glycolysis, the TCA cycle, and oxidative phosphorylation. Cancer cells rewire metabolic pathways to favour biomass production over ATP generation which is required to support an increased proliferative rate. Increased nutrient uptake is primarily used to fuel anabolic branchpoints from glycolysis and the TCA cycle. This reprogramming of cellular metabolism supports tumour development and progression. The figure was created with BioRender.com. acetyl-CoA: acetyl-coenzyme A; succiyl-CoA: succiyl-coenzyme A; TCA: tricarboxylic acid; 1C: one carbon; PPP: pentose phosphate pathway

Figure 3

Signalling pathways that support tumour biomass production regulated by aspirin. Tumour cells frequently have aberrant activation of key signalling pathways such as the Wnt, mTOR, NF-κB, and HIF-1α. Aspirin has been shown to regulate these important oncogenic drivers and a number of downstream metabolic enzymes leading to a profound effect on metabolic reprogramming. The figure includes metabolic enzymes regulated by aspirin (in bold), signalling pathways regulated by aspirin and their downstream effect on metabolism, and key biosynthetic branchpoints. The figure was created with BioRender.com. HK2: hexokinase 2; G6P: glucose-6-phosphate; PFK1: phosphofructokinase 1; PDH: pyruvate dehydrogenase; PDK1: PDH kinase 1; α-KG: α-ketoglutarate