Studies On The Anti-angiogenesis Mechanism Of Hsp90 Inhibitor In Breast Cancer In Vivo

Breast cancer is a melignant cancer for women. Chemotherapy method has been still the mained so far. However, for the localization, conventional chemotherapy cannot reach certain curative effects. The programs of inhibiting the tumor angiogenesis, which specific to act on tumor cell and tissues with less side-effect on normal tissue, have already become a hot issue of Anti-tumor drugs research. ObjectiveTo investigate the effects of Hsp90 inhibitor in vivo and explore the mechanism of anti-angiogenesis. Methods 1. Western Blot was performed to detect the active of AT533 on MDA-MB-231 and MCF-7 in vitro under hypoxia conditions. 2. AT533 and BJ-B11 were exerted on breast cancer in vivo with the xenografted model of MDA-MB-231 cell line on BABL/c nude mice. 3. HE was used for staining section of breast cancer which cured by AT533 or BJ-B11. 4. Immunohistochemical and Western Blot were used to detect the changes of HIF-1α/VEGF signaling pathway on tumor tissue which cured by AT533 or BJ-B11 5. Immunohistochemical was used to research the effect of AT533 on apoptosis for breast cancer xenograft. Result 1. Hsp90 was broke in MDA-MB-231 treatment with AT533 and down-regulated in MCF-7 in vitro. AT533 couldalso inhibit the HIF-1α/VEGF signaling pathway and promote the protein ubiquitination in vitro. 2. Breast cancer animal model was inhibited by AT533 or BJ-B11 in vivo. 3. The angiogenesis in breast cancer was inhibited by AT533 or BJ-B11, which contribute to tissue ischemia in vivo. 4. The HIF-1α/VEGF signaling pathway was suppressed by AT533 or BJ-B11 in vivo. 5. AT533 was contributed to the apoptosis for breast cancer xenograft in vivo. ConclusionAT533 regulate the HIF-1α/VEGF signaling pathway with which activated by hypoxia and the promoting ubiquitination. The mechanism is involved in the suppression of Hsp90 so that the HIF-1α/VEGF signaling pathway downregulation,, angiogenesis suppression and apoptosis of tumour cells. BJ-B11, the prodrug of AT533, has the similar effect with AT533 in vivo.