Contribution of uric acid to cancer risk, recurrence, and mortality

UA is derived exclusively from the oxidation of xanthine and hypoxanthine by XOR [1], and pharmacological inhibition of XOR has been used extensively for the management of hyperuricemic disorders such as gout, nephrolithiasis, some cases of acute and chronic kidney disease, ischemia-reperfusion disorders, and others [2,3]. In 1982 UA was hypothesized by Ames et al. to provide a primary defense against human cancer based upon its capacity to scavenge singlet oxygen, its capacity to inhibit lipid peroxidation, and its high serum concentration in humans [4]. Extensive support for the physiological antioxidant function of UA was generated in the ensuing dozen years since publication of this hypothesis, and the protective antioxidant properties of UA have been identified in many different organ systems [5]. Nonetheless, elevated serum urate, the dominant monosodium form of UA at physiological pH, was found to exhibit strong statistical association with increased premature cancer death in both men and women [6-8] suggesting a more complex role for UA in cancer biology than that of a general antioxidant (Table？ 1).In humans, normal SUA levels are commonly between 178 and 360？μM, (3 and 6.8？mg/dl) with higher levels found in males and postmenopausal females than in premenopausal females. Frank hyperuricemia (SUA levels > 360？μM) can reach levels of 700？μM or higher and are associated with increasing risk for gout and acute kidney injury arising from the deposition of monosodium urate (MSU) crystals in the renal tubules and interstitium [9]. Mechanisms inducing MSU crystal formation and deposition are complex and not simply an automatic consequence of hyperuricemia [10]. More recently there has been increasing interest that high to high normal levels of SUA (310–330？μM), below those associated with MSU crystal deposition, may have contributory roles in acute renal injury [11], chronic kidney disease [12,13], hypertension [14], cardiovascular disease (CVD) [15-17], and MetS [