Therapeutic value of orally administered silibinin in renal cell carcinoma: manipulation of insulin-like growth factor binding protein-3 levels.

Abstract

To investigate if the feeding of silibinin (an anticancer flavonoid) to mice inhibits in vivo renal cell carcinoma (RCC) growth via changes in insulin-like growth factor binding protein-3 (IGFBP-3) levels. Male severe combined immunodeficiency disease (SCID) mice (7 weeks old), with left kidneys injected with 1 million SN12K1 cells, were fed a silibinin-containing diet (0.1%, 0.2% and 0.4% w/w) or control AIN-93G diet for 39 days from 1 day after tumour engraftment. There was a reduction in tumour deposits and tumour kidney weight in SCID mice fed with a 0.4% silibinin-containing diet compared to those fed the control diet. Mice with tumour injection (silibinin or control-diet group) had constant total body weight and food consumption. The mean plasma and tumourous kidney silibinin concentrations, as measured by high-pressure liquid chromatography-tandem mass spectrometry, increased with escalating doses of silibinin. Using real-time polymerase chain reaction and enzyme-linked immunosorbent assay, the mean tissue IGFBP-3 mRNA (in SN12K1-implanted kidney) and plasma IGFBP-3 levels increased in mice fed with 0.1% silibinin (tumour IGFBP-3 mRNA levels, 156% higher vs control-diet group, P = 0.007; and plasma IGFBP-3 levels, 61% higher vs control-diet group, P = 0.002) but not in mice fed with the higher silibinin pellet strengths. Oral administration of silibinin suppressed local and metastatic tumour growth in vivo in an orthotopic xenograft model of RCC. This anti-neoplastic action of silibinin might involve IGFBP-3. The exact mechanism through which IGFBP-3 promotes silibinin's anticancer effects warrants further investigation.