Mechanistic study of BNP7787-mediated cisplatin nephroprotection: modulation of gamma-glutamyl transpeptidase

Abstract

The GGT xenobiotic metabolism pathway is postulated to be a major toxification pathway for cisplatin nephrotoxicity, and BNP7787 may play a novel and critical therapeutic role in the modulation of GGT activity. We further postulate that there are two general mechanisms for BNP7787-mediated nephroprotection against cisplatin-induced nephrotoxicity involving this pathway. First, the active BNP7787 pharmacophore, mesna, produces an inactive mesna-cisplatin conjugate that is not a substrate for the GGT toxification pathway (GGT xenobiotic metabolism pathway) and, second, BNP7787-derived mesna-disulfide heteroconjugates may serve as selective, potent inhibitors of GGT, possibly resulting in nephroprotection by a novel means.

Accumulation of BNP7787 in Human Renal Proximal Tubule Cells

“…Additionally, some BNP7787-derived mesna-disulfide heteroconjugates, formed as a result of the extracellular reactions between BNP7787 and physiological thiols or between BNP7787-derived mesna and physiological disulfides, have been shown to inhibit GGT and APN. 15,16 Results of the studies herein indicate that the amount of BNP7787-derived mesna detected in lysates isolated from human HK-2 cells incubated with BNP7787 (10 mM) increased as a function of increasing incubation time. Cells generally maintain a strongly reducing intracellular environment 14,30 ; therefore, we propose that once BNP7787 enters the cell, it is likely to be reduced to the free thiol form metabolite, mesna.…”

“…In animal studies, Ormstad and Uehara 14 noted that transmembranal uptake of dimesna (BNP7787) is expected to require energy and involve an active transport mechanism; they demonstrated the uptake of BNP7787 in rat kidney perfusions and rat kidney cells. Additionally, in vitro, we have observed that BNP7787 and BNP7787-derived mesna-disulfide heteroconjugates can inhibit human γ-glutamyltranspeptidase (GGT) and aminopeptidase N (APN) enzymes 15,16 that are postulated to be important in converting cisplatin to a nephrotoxigenic species. [22][23][24][25][26][27][28][29] If there is metabolism and local action and/or local uptake of BNP7787 by renal tubular cells, it is likely that a protective mechanism exists, whereby BNP7787's disulfide bond is reduced to yield BNP7787-derived mesna, the reactive thiol (Fig.…”

“…8,10 BNP7787 metabolism appears to involve nonenzymatically mediated thiol and disulfide transfer reactions that yield BNP7787-derived mesna-disulfide heteroconjugates. 8,9,15,16 Transport-mediated uptake is likely the major pathway of cisplatin uptake in renal tubular cells, although passive uptake also occurs. 17,18 Possible routes for uptake of BNP7787 or BNP7787-derived mesna-disulfide heteroconjugates in the kidney include transport into the cell, 19 uptake by organic anion transporters 1, 3, and 4, 20 and free glomerular filtration (BNP7787 is a small molecular weight anion and is expected to be freely filtered by the glomeruli).…”

BNP7787-Mediated Modulation of Paclitaxel- and Cisplatin-Induced Aberrant Microtubule Protein Polymerization In vitro

“…In an additional phase III clinical trial, treatment with BNP7787 seemed to significantly improve 1-year survival of patients with advanced primary adenocarcinoma of the lung who were being treated with cisplatin and paclitaxel regimens in the first-line setting (36). Previous studies have suggested that BNP7787 seems to have significant cisplatin nephroprotective benefits (11,37,38,40,46,49,50). Based on data presented herein, we propose that BNP7787 interactions with MTP may be one mechanism through which BNP7787 may act to protect against taxane-or platinum-induced neurotoxicity by normalizing paclitaxel-induced hyperpolymerization of MTP and by forming BNP7787-derived mesna in vivo, which reacts with and inactivates the highly reactive monoaquocisplatin species.…”

Carvedilol protects the kidneys of tumor-bearing mice without impairing the biodistribution or the genotoxicity of cisplatin

“…Minimization of renal toxicity is essential to improve the effectiveness of cisplatin chemotherapy and the quality of life of patients (Hausheer et al, 2010).…”