Uroprotective mechanisms of natural products against cyclophosphamide-induced urinary bladder toxicity: A comprehensive review

Abstract

One of the widely used anticancer drugs for the treatment of various neoplasms is cyclophosphamide (CYP). The inactive prodrug CYP is metabolized by cytochrome P450 enzyme into active metabolites, phosphoramide mustard and acrolein. The accumulation of acrolein metabolite inside the urothelium results in hemorrhagic cystitis (HC) which is a urotoxic adverse effect associated with the use of CYP. To counteract the occurrence of HC induced by CYP, Mesna is usually used, with allergic reactions reported in some cases. Therefore, several natural products have drawn much attention as alternative safe therapies to reduce the urotoxicity produced from the use of CYP. This review will focus on certain uroprotective mechanisms related to some medicinal plants that are used to ameliorate the CYP-induced urotoxicity in experimental models. The mechanisms involving oxidative stress, inflammation, immune system, apoptosis, DNA fragmentation, uroplakins, purinergic signaling and muscarinic receptors, and CytoP450 metabolism are discussed.

Mechanism of the Immunomodulatory Effect of the Combination of Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus on Immunocompromised Rats

“…In addition to probiotics (27,28,(45)(46)(47), some other orally administered agents, such as plant extracts, active components, and their derivatives, were shown to reduce immunotoxicity of cyclophosphamide in animals (48,49). The effects of these substances are mediated by antioxidant and anti-inflammatory activities, protection of intestinal mucosal barrier, and maintenance of a balance of intestinal microbiota but are not limited to these mechanisms (48,49). Nevertheless, the safety and effectiveness of most of these agents require further verification in humans.…”

Could Mesna and Celery Seed Cotherapy Modulate Oxidative Stress and Inflammation of the Urinary Bladder Induced by Ifosfamide in Rabbits?

“…At the same time, the pathogenesis of HC is influenced by the toxic effects of acrolein and the cascade of cellular inflammatory reactions on the urothelium of UB, with consequent injury of these tissues, which are evoked by the release of numerous proinflammatory mediators. 29 Moreover, acrolein activates the inflammatory mediators such as the nuclear factor-kB (NF-kB) and TNF-α, which initiate lipids peroxidation and exaggerate oxidative stress. After entering the UB, acrolein increases the production of ROS in the urothelium, reacts with glutathione and aldehyde dehydrogenase to produce the toxic acrolein metabolites, which are responsible for the overproduction of free oxygen radicals by the urothelium.…”

Effect of a Low Dose of Carvedilol on Cyclophosphamide-Induced Urinary Toxicity in Rats—A Comparison with Mesna

“…In the phase of clinical symptoms, erosions and ulcerations in the urothelium are present, which results in pain and bladder dysfunction. The last phase is the healing phase, involving fibroblasts and locally released growth factors [7,[31][32][33].…”

“…In the phase of clinical symptoms, erosions and ulcerations in the urothelium are present, which results in pain and bladder dysfunction. The last phase is the healing phase, involving fibroblasts and locally released growth factors [7,[31][32][33]. Acrolein is not solely the product of cyclophosphamide liver metabolism, but is also formed endogenously during oxidative stress-mediated lipid peroxidation, myeloperoxidase-mediated oxidation of amino acids, or may be of the environmental origin as a pollutant in tobacco smoke or from other sources [34][35][36].…”