Chemoprotection byd-methionine against cisplatin-induced side-effects: insight from in vitro studies using human plasma

Abstract

Animal studies have shown that the nephrotoxicity and ototoxicity of the anti-cancer drug cisplatin (CP) can be ameliorated by the co-administration with D-methionine. The molecular mechanisms of this activity, however, are not well understood. Since CP is intravenously administered, the underlying chemistry may involve the interaction of CP-derived Pt-species with D-methionine in the bloodstream. Our previous studies have shown that the chemoprotective agents N-acetyl-l-cysteine and sodium thiosulfate modulate the metabolism of CP in human plasma in vitro, albeit in a different manner. Using a metallomics approach, we show that the incubation of human plasma with D-methionine and CP (molar ratio of 20 : 1) leads to the formation of a Pt-D-methionine complex independent of the order of addition. These results were corroborated by analogous experiments that were carried out using PBS-buffer instead of plasma. In addition, CP and D-methionine were added simultaneously to PBS-buffer and samples were analyzed at certain time intervals by the same metallomics method and LC-ESI-MS over a ∼21 h time period. Whereas the intermediate [Pt(NH3)Cl(D-methionine)](+) species was detected between 1-4 h, only the terminal [Pt(D-methionine)2](+) complex was present 21 h later. Combined, these studies demonstrate that in plasma and at the 20 : 1 D-methionine : CP molar ratio, an early CP hydrolysis product reacts with D-methionine to form a 1 : 1 complex that is followed by the formation of a 2 : 1 compound at a later time point. The formation of these Pt-D-methionine species may therefore play an important role in the processes by which D-methionine protects mammalian organisms against CP-induced toxicities.

He-Wei granules (HWKL) combat cisplatin-induced nephrotoxicity and myelosuppression in rats by inhibiting oxidative stress, inflammatory cytokines and apoptosis

“…1 Although many years have passed since then, cisplatin remains one of the most widely used drugs to treat a variety of human cancers in clinical situations although there are now many platinum analogues available because of their potent anticancer effects and low cost. [1][2][3][4] However, cisplatin can produce severe toxicity during chemotherapy despite its marked antineoplastic properties, including nausea, emesis, nephrotoxicity, myelosuppression and ototoxicity. 3 As a dose-dependent antineoplastic drug, the therapeutic efficacy of cisplatin is improved by increasing the dose although this can lead to more severe toxicity.…”

“…[1][2][3][4] However, cisplatin can produce severe toxicity during chemotherapy despite its marked antineoplastic properties, including nausea, emesis, nephrotoxicity, myelosuppression and ototoxicity. 3 As a dose-dependent antineoplastic drug, the therapeutic efficacy of cisplatin is improved by increasing the dose although this can lead to more severe toxicity. 5 More than 70% of pediatric patients receiving cisplatin experience renal dysfunction and due to severe toxicity, the use of cisplatin is restricted.…”

Physiologically relevant plasma d , l -homocysteine concentrations mobilize Cd from human serum albumin

“…The hCys control experiment was carried out by adding 100 L of the hCys stock solution to 900 L of PBS buffer, giving a final concentration of 0.5 mM. The actual experiment involved the addition of 900 L of the HSA stock solution to 100 L of the hCys stock solution (45 g HSA/L; 0.5 mM hCys), incubation at 37 • C followed by analysis of 0.5 mL aliquots after 5 min and 1 h. The SEC column that was employed was a Superdex 200 GL 10/300 size-exclusion column (flow rate 0.75 mL/min; 13 m particle diameter), which was connected to an ICP-AES as reported previously [50].…”

Ameliorative effect of an oxovanadium (IV) complex against oxidative stress and nephrotoxicity induced by cisplatin

“…The serendipitously discovered cisplatin (CDDP) triggered the discovery of other metal-based drugs, but still remains one of the most widely used anti-cancer drugs worldwide [1]. Despite its remarkable anti-neoplastic properties, CDDP therapy is associated with several adverse effects, including nephrotoxicity, ototoxicity, myelosuppression, and neurotoxicity [2].…”