Inhibitory effects of the Cimicifuga racemosa extract BNO 1055 (CR) on growth of androgen-induced prostate growth of the human prostate cancer cells LNCaP

We have recently shown that CR does not bind to estrogen or androgen receptors. Nevertheless, proliferation of the human prostate cancer derived LNCaP cells was significantly inhibited at extraordinary low concentrations. This prompted us to seek for the mechanisms by which CR exerts this putatively important phenomenon. Immature male rats were orally treated with testosterone (T) for 5 days and either co-treated with 0.5mg of the 5α-reductase inhibitor finasteride (Fin) or with 30mg of CR. Both, Fin and CR inhibited T-stimulated prostate weight and DHT formation in the prostate (p<0.05). The formation of 5α-androstane-3α,17β (3α-diol) in the prostate was also inhibited by Fin (p<0.05) but not by CR indicating that CR possibly not only inhibits 5α-reductase but stimulates 3β-hydroxysteroid dehydrogenase which would also result in increased 3β-diol formation, the endogenous ligand for ERß which mediates antiproliferative effects on prostate cells. These results encouraged us to transplant LNCaP cells into male immune-deficient nu/nu mice. After a subcutaneous inoculation of 1 mio cells 12 of 18 animals developed solid subcutaneous tumours while tumour development was seen in only 5 of 18 CR-treated animals. 5α-DHT as well as PSA in the serum and 5α-DHT in tumour extracts were significantly reduced by the CR treatment. It is concluded that CR is a potent 5α-reductase inhibitor thereby ameliorating the stimulatory effects of T on prostate cancer cell growth. The inhibitory effect by CR on PSA may be an additional antiproliferative effect because PSA is an enzyme which cleaves insulin-like growth factor-1 binding protein-3 (IGF1 BP3) thereby making more IGF1 locally available. IGF1 is a potent mitogen which stimulates LNCaP cell proliferation. Hence, inhibition of PSA secretion prevents the liberation of IGF1 and thereby reduces the stimulation of IGF1-mediated LNCaP cell proliferation. In addition, CR appears to stimulate formation of 3β-diol which would further inhibit prostate cancer cell proliferation.