Moser, Christian and Lang, Sven A. and Mori, Akira and Hellerbrand, Claus and Schlitt, Hans J. and Geissler, Edward K. and Fogler, William E. and Stoeltzing, Oliver (2008) 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. BMC CANCER, 8: 206. ISSN 1471-2407,
Full text not available from this repository. (Request a copy)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-1 alpha and STAT3 have been implicated in HCC progression, thus representing interesting targets for molecular targeted therapy. We hypothesized that therapeutic inhibition of HIF-1 alpha 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-1 alpha 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-1 alpha 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-1 alpha and STAT3 in human HCC cells and leads to reduced tumor growth and vascularization in vivo. Hence, inhibition of HIF-1 alpha and STAT3 could prove valuable for therapy of hepatocellular carcinoma.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; RANDOMIZED CONTROLLED TRIAL; FACTOR 1-ALPHA HIF-1-ALPHA; TUMOR-GROWTH; VEGF EXPRESSION; PANCREATIC-CANCER; MULTIPLE-MYELOMA; GENE-EXPRESSION; AUTOCRINE LOOP; BREAST-CANCER; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Oct 2020 07:42 |
| Last Modified: | 28 Oct 2020 07:42 |
| URI: | https://pred.uni-regensburg.de/id/eprint/30607 |
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