Abstract
Abstract Background: Class III β tubulin (TUBB3) reduces microtubule stability and confers resistance to microtubule stabilizing taxanes, including paclitaxel and docetaxel. Expression of vascular endothelial growth factor (VEGF) is highly regulated by hypoxia and the regulation of VEGF expression by hypoxia is mediated by a hypoxia inducible factor-1a(HIF-1a), which increase transcription of the VEGF gene. Recent report showed hypoxia induces expression of TUBB3 by HIF-1a. Inhibition of VEGF system may decrease the expression of HIF-1a and TUBB3. This study was undertaken to investigate the synergistic antitumor effects of bevacizumab and palitaxel on TUBB3 expressing gastric cancer cells. Methods: We evaluated the expressions of TUBB3 and HIF-1a under normoxic and hypoxic conditions in human gastric cancer cells. The chemoresistance of TUBB3 to paclitaxel was checked through knockdown of TUBB3. Expressions of TUBB3 and HIF-1a were measured under blocking of VEGFR1/2 with anti-FLT1 and anti-KDR antibodies. The effects of bevacizumab and paclitaxel on expressions of TUBB3 and HIF1a were monitored by western blot and MTT assay. Results: The chemosensitivities to paclitaxel were increased by siTUBB3. Elevated expressions of TUBB3 and HIF-1a in gastric cancer cells under hypoxic conditions were reduced in the prescence of anti-KDR and anti-FLT1 antibodies. When we added the bevacizumab to paclitaxel, the protein expressions of TUBB3 and HIF-1a in gastric cancer cells under hypoxic conditions were significantly decreased as compared with paclitaxel alone. Apoptosis of gastric cancer cells were more increased in a combined treatment with bevacizumab and paclitaxel than paclitaxel alone. Tyrosine phosphorylation of Erk and Akt was also measured in gastric cancer cells under hypoxic conditions in the absence or prescence of anti-KDR, anti FLT-1 and paclitaxels. Hypoxia induced phosphorylation of Erk and Akt in gastric cancer cells was more decreased by addition of anti FLT-1 and anti KDR antibodies to paclitaxel as compared with paclitaxel alone. Conclusion: Our experiments show that a VEGF/VEGFR/pERK and, or pAKT pathway is activated by hypoxic gastric cancer cells to induce HIF-1a and TUBB3 expressions. Combined treatment with paclitaxel and bevacizumab, a recombinant humanized monoclonal antibody that binds to VEGF, synergistically decreased the expressions of HIF-1a and TUBB3 in gastric cancer cells in hypoxic conditions. With increasing use of taxanes in the treatment of gastric cancer, this study showed the potential synergistic antitumor effects of bevacizumab and paclitaxel in a TUBB3, a marker of resistance to paclitaxel, overexpressing gastric cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4252. doi:10.1158/1538-7445.AM2011-4252
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