Potent inhibition of tumoral hypoxia-inducible factor 1α by albendazole
| Autor: | Marianne S. Poruchynsky, David L. Morris, Samina Badar, Kiran T. Wangoo, Mohammad H. Pourgholami, Zhao Y. Cai |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Vascular Endothelial Growth Factor A
Cancer Research Time Factors Angiogenesis Down-Regulation Mice Nude Angiogenesis Inhibitors Deferoxamine Pharmacology Albendazole lcsh:RC254-282 Metastasis Mice chemistry.chemical_compound Downregulation and upregulation In vivo Cell Line Tumor Genetics medicine Animals Humans RNA Messenger Ovarian Neoplasms Mice Inbred BALB C Dose-Response Relationship Drug Neovascularization Pathologic business.industry lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Xenograft Model Antitumor Assays Cell Hypoxia Vascular endothelial growth factor Vascular endothelial growth factor A Oncology Hypoxia-inducible factors chemistry Female Ovarian cancer business Research Article |
| Zdroj: | BMC Cancer BMC Cancer, Vol 10, Iss 1, p 143 (2010) |
| ISSN: | 1471-2407 |
| DOI: | 10.1186/1471-2407-10-143 |
| Popis: | Background Emerging reports suggest resistance, increased tumor invasiveness and metastasis arising from treatment with drugs targeting vascular endothelial growth factor (VEGF). It is believed that increased tumoral hypoxia plays a prominent role in the development of these phenomena. Inhibition of tumoral hypoxia inducible factor (HIF-1α) is thus becoming an increasingly attractive therapeutic target in the treatment of cancer. We hypothesized that the anti-VEGF effect of albendazole (ABZ) could be mediated through inhibition of tumoral HIF-1α. Method In vitro, the effects of ABZ on HIF-1α levels in human ovarian cancer cells (OVCAR-3) were investigated using hypoxic chamber or desferrioxamine (DFO) induced-hypoxia. In vivo, the effects of ABZ (150 mg/kg, i.p., single dose) on the tumor levels of HIF-1α and VEGF protein and mRNA were investigated by western blotting, RT-PCR and real time-PCR. Results In vitro, ABZ inhibited cellular HIF-1α protein accumulation resulting from placement of cells under hypoxic chamber or exposure to DFO. In vivo, tumors excised from vehicle treated mice showed high levels of both HIF-1α and VEGF. Whereas, tumoral HIF-1α and VEGF protein levels were highly suppressed in ABZ treated mice. Tumoral VEGFmRNA (but not HIF-1αmRNA) was also found to be highly suppressed by ABZ. Conclusion These results demonstrate for the first time the effects of an acute dose of ABZ in profoundly suppressing both HIF-1α and VEGF within the tumor. This dual inhibition may provide additional value in inhibiting angiogenesis and be at least partially effective in inhibiting tumoral HIF-1α surge, tumor invasiveness and metastasis. |
| Databáze: | OpenAIRE |
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