Pharmacology and cellular/molecular mechanisms of action of aspirin and non-aspirin NSAIDs in colorectal cancer
Abstract
Colorectal cancer (CRC) and colorectal adenomas have in common a dysfunctional adenomatous polyposis coli suppressor gene (APC). This allows for activation of the oncogenic Wnt/β-catenin pathway, resulting in cytosolic accumulation of β-catenin, its translocation to the nucleus and action as a cofactor for stimulation of gene transcription. Pharmacological approaches of CRC-chemoprevention are focused to prevention of this β-catenin-mediated oncogenic signalling. Among upregulated genes in tumour tissue is COX-2 which synthesises large amounts of PGE(2). PGE(2) inhibits apoptosis, acts proinflammatory and immunosuppressive and stimulates tumour angiogenesis and proliferation. In addition, COX-2 causes oxidation (activation) of cocarcinogens. Aspirin and non-aspirin NSAIDs inhibit COX-2, subsequent PGE(2) formation and action by transcriptional and non-transcriptional mechanisms. These also include inhibition of generation of sphingosine-1-phosphate, an amplifier of these reactions and stimulation of NSAID-induced gene (NAG-1) which acts as an inhibitor. Aspirin additionally acetylates COX-2, resulting in generation of 'aspirin-triggered' lipoxins (ATL), a new class of anti-inflammatory/antitumour compounds. COX-1 inhibition might also contribute to antitumour effects of aspirin, for example at low-dose aspirin. Experimental evidence suggests additional COX independent actions of aspirin and non-aspirin NSAIDs on oncogenic signalling. This includes modifications of…
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