ENMD-1198, a novel tubulin-binding agent reduces HIF-1alpha and STAT3 activity in human hepatocellular carcinoma(HCC) cells, and inhibits growth and vascularization in vivo

• Published in: BMC cancer 2008-07, Vol.8 (1), p.206-206, Article 206
• Main Authors: Moser, Christian, Lang, Sven A, Mori, Akira, Hellerbrand, Claus, Schlitt, Hans J, Geissler, Edward K, Fogler, William E, Stoeltzing, Oliver
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - pharmacology; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - pharmacology; Carcinoma, Hepatocellular - blood; Carcinoma, Hepatocellular - blood supply; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; DNA binding proteins; Dosage and administration; Drug therapy; Estrenes - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Health aspects; Hepatoma; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Liver Neoplasms - blood; Liver Neoplasms - blood supply; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Neovascularization, Pathologic - drug therapy; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Transcriptional Activation - drug effects; Tubulin Modulators - pharmacology; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - genetics
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-8-206

Hepatocellular carcinoma (HCC) represents a highly vascularized tumor entity and the process of angiogenesis is essential for the growth of HCC. Importantly, the pro-angiogenic transcription factors HIF-1alpha and STAT3 have been implicated in HCC progression, thus representing interesting targets for molecular targeted therapy. We hypothesized that therapeutic inhibition of HIF-1alpha could be achieved by using a novel tubulin-binding agent (ENMD-1198). ENMD-1198 is an analog of 2-methoxyestradiol (2ME2) with antiproliferative and antiangiogenic activity. The human HCC cell lines HUH-7 and HepG2 were used for experiments. Effects of ENMD-1198 on constitutive and inducible (hypoxia, growth factors) activation of signaling cascades, including HIF-1alpha and STAT3, were investigated by Western blotting. Changes in VEGF expression were determined by real-time PCR. Effects of ENMD-1198 on cancer cell migration and invasion were evaluated in in vitro-assays. The growth-inhibitory effects of ENMD-1198 (200 mg/kg/day) were determined in a subcutaneous tumor model (HUH-7). ENMD-1198 inhibited the phosphorylation of MAPK/Erk, PI-3K/Akt and FAK. Moreover, activation of HIF-1alpha and STAT3 was dramatically reduced by ENMD-1198, which resulted in lower VEGF mRNA expression (P < 0.05). In addition, tumor cell migratory and invasive properties were significantly inhibited (P < 0.05, for both). In vivo, treatment with ENMD-1198 led to a significant reduction in tumor growth, tumor vascularization, and numbers of proliferating tumor cells (P < 0.05 for all). The novel microtubule destabilizing agent ENMD-1198 is suitable for inhibiting HIF-1alpha and STAT3 in human HCC cells and leads to reduced tumor growth and vascularization in vivo. Hence, inhibition of HIF-1alpha and STAT3 could prove valuable for therapy of hepatocellular carcinoma.