Gentisic Acid, a Quinonoid Aspirin Metabolite in Cancer Prevention and Treatment. New Horizons in Management of Brain Tumors and Systemic Cancers

Gentisic Acid (GA) is an endogenously synthesized quinonoid phenolic acid in plants, where it functions as an immune molecule against viral plant pathogens via modifying microRNAs. In mammalians, GA is both consumed from exogenous sources (from fruits and vegetables) and produced endogenously as an endogenous siderophore and as a byproduct of tyrosine catabolism. Besides the edible plants, aspirin is also an important source of GA, since its catabolism produces GA. Noteworthy, humans with variant alleles of CYP2C9 which are incapable to produce GA during aspirin catabolism do not benefit from aspirin in reduction of adenomas in the large bowel. In past, GA was successfully used in the treatment of rheumatological diseases in humans with high biosafety. GA has an affinity to connective tissue proteins and a higher retention of exogenous GA was demonstrated in humans with cancer. GA has both direct and indirect strong antioxidant effects as a free radical scavenger molecule and as an agonist of NRF2 (Nuclear factor erythroid-derived 2-like 2), an important transcription factor which regulates synthesis of antioxidant molecules. GA blocks cancer promotion in animal models in association with reduction of free radical products and stimulating antioxidant molecules. GA also exerts prominent anti-inflammatory effects while stimulating elements of acquired immunity, lymphocytes; which likely occur due to its strong efficacies to block cyclooxygenases, 12-lipoxygenase and acting as a ligand of GPR35/CXCR8. GA also specifically inhibit protumorigenic signaling of Fibroblast Growth Factor (FGF) and cyclin-dependent kinase-1 (CDK1). Sulfonated derivative of GA (2,5-dihydroxyphenylsulfonate, dobesilic acid) blocks subcutaneous growth of C6 glioma; and GA also acts as an agonist of Vasoactive Intestinal Polypeptide (VIP) pathway, which suppresses invasion of glioma cells in vitro. GA also inhibits OAT3/ SLC22A8, which involves efflux of chemotherapeutics from the brain which may help to achieve therapeutic concentrations of anticancer agents in brain tumors. In future, combined aspirin-GA preparates may be tested for potential activity in cancer prevention and treatment.