Inhibition of growth and regulation of IGFs and VEGF in human prostate cancer cell lines by shikonin analogue 93/637 (SA)

Background - Insulin-like growth factors (IGFs) are important mitogens and are involved in normal and malignant cellular proliferation. IGFs and IGF b inding proteins (IGFBPs) regulate the prostatic cell growth and reduction/b locking of IGFs has been suggested to be of therapeutic value in prostate c ancer beta,beta-dimethyl acryl shikonin, an extract from the roots of plant Amebia nobilis has been shown to have anticancer properties but was found to be toxic. Subsequently, several analogues of beta,beta-dimethyl acryloyl shikonin were synthesized and one of them shikonin analogue 93/637 (SA) wa s significantly less toxic compared to beta,beta-dimethyl acryloyl shikonin . Materials and Methods - We have investigated the effect of SA on prostate cancer cell (DU 145, LNCaP and PC-3) growth and expression of IGFs (IGF-I, IGF-II and IGF-I receptor (IGF-IR)), IGFBP-3 and vascular endothelial grow th factor (VEGF). Results - SA had growth inhibitory effect on PC-3 cells i n a dose dependent manner. It also showed slight inhibitory effect on the g rowth of DU 145 and LNCaP cells at low doses ranging from 250 nM to 1 mu M and has moderate inhibitory effect at concentrations 2.5 mu M and above. La ctate dehydrogenase (LDH) activity assays indicated cellular damage, only a t higher concentrations of SA that are greater than 1 mu M. Gene expression studies by RT-PCR have demonstrated a decrease in mRNAs of IGF-II in DU 14 5, IGF-I, and IGF-IR in LNCaP, and IGF-II and VEGF in PC-3 cells and an inc rease in IGFBP-3 in both DU 145 and PC-3 cells by treatment with SA. Conclu sions - The results demonstrate the inhibitory effect of SA on cellular gro wth and ICFs specifically in PC-3 cells and suggest a potential therapeutic use in treatment of prostate cancer.