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 binding proteins (IGFBPs) regulate the prostatic cell growth and reduction/blocking of IGFs has been suggested to be of therapeutic value in prostate cancer. beta,beta-dimethyl acryl shikonin, an extract from the roots of plant Arnebia nobilis has been shown to have anticancer properties but was found to be toxic. Subsequently, several analogoues of beta,beta-dimethyl acryloyl shikonin were synthesized and one of them shikonin analogue 93/637 (SA) was significantly less toxic compared to beta,beta-dimethyl acryloyl shikonin.


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 growth factor (VEGF).


RESULTS
SA had growth inhibitory effect on PC-3 cells in a dose dependent manner. It also showed slight inhibitory effect on the growth of DU 145 and LNCaP cells at low doses ranging from 250 nM to 1 microM and has moderate inhibitory effect at concentrations 2.5 microM and above. Lactate dehydrogenase (LDH) activity assays indicated cellular damage, only at higher concentrations of SA that are greater than 1 microM. Gene expression studies by RT-PCR have demonstrated a decrease in mRNAs of IGF-II in DU 145, IGF-I, and IGF-IR in LNCaP, and IGF-II and VEGF in PC-3 cells and an increase in IGFBP-3 in both DU 145 and PC-3 cells by treatment with SA.


CONCLUSIONS
The results demonstrate the inhibitory effect of SA on cellular growth and IGFs specifically in PC-3 cells and suggest a potential therapeutic use in treatment of prostate cancer.
Gaddipati
J P
JP
Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Mani
H
H
Shefali
Raj
K
K
Mathad
V T
VT
Bhaduri
A P
AP
Maheshwari
R K
RK
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000235:genetics*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics*; D008297:Male; D009285:Naphthoquinones / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D017451:Receptors, Somatomedin / Q000235:genetics*; D013002:Somatomedins / Q000235:genetics*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000972:Antineoplastic Agents, Phytogenic; D016228:Endothelial Growth Factors; D018972:Insulin-Like Growth Factor Binding Protein 3; D008222:Lymphokines; D009285:Naphthoquinones; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; D013002:Somatomedins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C016101:shikonin; D007770:L-Lactate Dehydrogenase