Journal Article

STAT3 inhibitor WP1066 as a novel therapeutic agent for renal cell carcinoma

Asano, T, Hayakawa, M, Horiguchi, A, Ito, K, Sato, A, Kuroda, K, Sumitomo, M, Asakuma, J

2010

Overview

Background: Signal transducer and activator of transcription 3 (STAT3) regulates the expression of genes that mediate cell survival, proliferation, and angiogenesis and is aberrantly activated in various types of malignancies, including renal cell carcinoma (RCC). We examined whether it could be a novel therapeutic target for RCC by using the STAT3 inhibitor WP1066. Methods: The antitumour activities and related mechanisms of WP1066 were investigated in vitro on renal cancer cell lines and in vivo on murine xenografts. Results: In Caki-1 and 786-O renal cancer cells, 5  μ M WP1066 prevented the phosphorylation of STAT3, and 2.5  μ M WP1066 significantly ( P <0.01) inhibited cell survival and proliferation. WP1066 suppressed the expression of Bcl-2, induced apoptosis, and inhibited the basal and hypoxia-induced expression of HIF1 α and HIF2 α , as well as vascular endothelial growth factor secretion into cell culture medium. Human umbilical vascular endothelial cells cocultured with media from WP1066-treated cells showed significantly reduced tubulogenesis ( P <0.05). Systemic oral administration of WP1066 to mice for 19 days significantly inhibited the growth of Caki-1 xenograft tumours ( P <0.05), and pathological analysis of xenografts of WP1066-treated mice showed decreased immunostaining of phosphorylated STAT3 and reduced length of CD34-positive vessels ( P <0.05). Conclusion: Our results suggest that using WP1066 to inhibit the STAT3 signalling pathway could be a novel therapeutic strategy against RCC.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/436/2388 / 692/699/67/589/1588/1351 / Angiogenesis / Animals / Antibodies / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Apoptosis / Apoptosis - drug effects / Basic Helix-Loop-Helix Transcription Factors - genetics / Basic Helix-Loop-Helix Transcription Factors - metabolism / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer therapies / Carcinoma, Renal Cell - drug therapy / Carcinoma, Renal Cell - genetics / Carcinoma, Renal Cell - metabolism / Cell culture / Cell cycle / Cell Proliferation - drug effects / Cell Survival - drug effects / Cells, Cultured / Cytokines / Drug Resistance / Epidemiology / Gene Expression Regulation, Neoplastic - drug effects / Humans / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Kidney cancer / Kidney Neoplasms - drug therapy / Kidney Neoplasms - genetics / Kidney Neoplasms - metabolism / Kidneys / Kinases / Medical prognosis / Medical research / Medical sciences / Mice / Mice, Nude / Molecular Medicine / Neovascularization, Pathologic - drug therapy / Neovascularization, Pathologic - pathology / Nephrology. Urinary tract diseases / Oncology / Phosphorylation / Proteins / Pyridines - pharmacology / Pyridines - therapeutic use / STAT3 Transcription Factor - antagonists & inhibitors / Translational Therapeutics / Tumors / Tumors of the urinary system / Tyrphostins - pharmacology / Tyrphostins - therapeutic use / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - genetics / Vascular Endothelial Growth Factor A - metabolism / Xenograft Model Antitumor Assays