Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity

Abstract

Summary Cisplatin is one of the most active cytotoxic agents in the treatment of testicular cancer, but its clinical use is associated with side-effects such as ototoxicity, neurotoxicity and nephrotoxicity. Long-term kidney damage from cisplatin particularly affects the proximal tubular apparatus and can be detected by increased urinary excretion of brush-border enzymes, such as L-alanine-aminopeptidase (AAP), and magnesium. In the current study, the flavonoid silibinin was used as a nephroprotectant for cisplatin-induced nephropathy in a rat animal model. Infusion of silibinin before cisplatin results in a significant decrease in glomerular (indicated by creatinine clearance and serum urea level) and tubular kidney toxicity (excretion of brush-border enzymes and magnesium). Silibinin given alone had no effect on renal function. In order to exclude an inhibition of the anti-tumour activity of cisplatin and 4-hydroperoxy-ifosfamide by coadministration of silibinin, in vitro studies were performed in three established human testicular cancer cell lines. Dose-response curves for cisplatin (3-30 000 nmol) combined with non-toxic silibinin doses (7.25 x 10-6 or 7.25 x 10-5 mol 1-1) did not deviate significantly from those of cisplatin alone as measured by relative cell survival during a 5 day assay using the sulphorhodamine-B staining technique. Also silibinin did not influence the cytotoxic activity of 4-hydroperoxy-ifosfamide (30-10 000 nmol) in vitro. In summary, these in vitro data rule out a significant inhibition of the anti-tumour activity of the major nephrotoxic components, cisplatin and 4-hydroperoxy-ifosfamide, by co-administration of silibinin in a human germ cell tumour cell line model. Together with these demonstrated cytoprotection effects in the rat animal model, these data form the basis for a randomised clinical trial of silibinin for the protection of cisplatin-associated nephrotoxicity in patients with testicular cancer.

Silymarin and epithelial cancer chemoprevention: How close we are to bedside?

“…Protective effects against cisplatin-or ifosfamide-induced nephrotoxicity without significant effect on the anti-tumor efficacy of these drugs have been reported in rat model of cisplatin-induced nephropathy. Results of these studies suggest the potential use of silymarin as protective agent against cisplatin-induced nephrotoxicity in cancer patients (Bokemeyer et al, 1996). Additionally, silymarin and its constituents have shown protective effects on rat cardiomyocytes exposed to doxorubicin due to its anti-oxidant, iron chelating and cell membrane stabilizing capacity (Chlopcikova et al, 2004).…”

Does silymarin affects neuroblastoma cell death via pro-inflammatory cytokine production with cisplatin?

“…Silmarinin kronik böbrek yetmezliği olan ve periton diyalizi gerçekleştirilen hastalarda alınması ile özellikle TNF-α'nın pro-enflamatuvar etkilerini baskılayarak bu hastalarda ortaya çıkan enflamatuvar anemiyi düzeltici etkisi belirlenmiştir (32) . Silmarinin radikal yakalayıcı ve antioksidan özel-likleri kanser hastalarında normal hücrelerin onkolojik tedaviye toleransla birlikte anti-kanser etkiyi bozmadan kanser tedavisine toleransı da arttırabile-ceği belirtilmektedir (33,34) . Bu yönüyle de silmarin hem kemoterapiye bağlı gelişen yan etkileri azaltarak doz azaltmaya gerek kalmadan etkin dozda kemoterapi uygulamasına izin vererek kemoterapi toleransı-nı arttırabilir hem de anti-kanser etkinliği ile kanser tedavisine katkı sağlayabilir (36) .…”

Nephroprotection by Theophylline in Patients with Cisplatin Chemotherapy

“…However, in general practice, a single-dose application of cisplatin as a 1-h infusion remains the common standard, and only dose fractionation over several days is being used in some cancer types (2,3). Experimental study drugs that may be useful in renal protection include BNP7787 (dimesna), selenium, amifostine, and silibinin (16,(27)(28)(29)(30)(32)(33)(34)(35).…”