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.

Abstract

BACKGROUND:

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.

METHODS:

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).

RESULTS:

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).

CONCLUSION:

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.

• Authors: Christian Moser, Sven A Lang, Akira Mori, Claus Hellerbrand, Hans J Schlitt, Edward K Geissler, William E Fogler, Oliver Stoeltzing
• Journal: BMC cancer (BMC Cancer) Vol. 8 Pg. 206 (Jul 23 2008) ISSN: 1471-2407 [Electronic] England
• PMID: 18651980 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-methoxyoestra-1,3,5(10),16-tetraene-3-carboxamide
• Angiogenesis Inhibitors
• Antineoplastic Agents
• Estrenes
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• STAT3 Transcription Factor
• STAT3 protein, human
• Tubulin Modulators
• Vascular Endothelial Growth Factor A

Topics

• Angiogenesis Inhibitors (pharmacology)
• Antineoplastic Agents (pharmacology)
• Carcinoma, Hepatocellular (blood, blood supply, drug therapy, pathology)
• Cell Line, Tumor
• Estrenes (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
• Liver Neoplasms (blood, blood supply, drug therapy, pathology)
• Neovascularization, Pathologic (drug therapy)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Transcriptional Activation (drug effects)
• Tubulin Modulators (pharmacology)
• Vascular Endothelial Growth Factor A (biosynthesis, genetics)