Alterations of Hypoxia-Induced Factor Signaling Pathway Due to Mammalian Target of Rapamycin (mTOR) Suppression in Ovarian Clear Cell Adenocarcinoma In Vivo and in Vitro Explorations for Clinical Trial

作者：Hirasawa Takeshi; Miyazawa Masaki; Yasuda Masanori^*; Shida Masako; Ikeda Masae; Kajiwara Hiroshi; Matsui Naruaki; Fujita Mariko; Muramatsu Toshinari; Mikami Mikio

来源：International Journal of Gynecological Cancer, 2013, 23(7): 1210-1218.

DOI：10.1097/IGC.0b013e31829d2d51

• Ovary
• Clear cell adenocarcinoma
• mTOR inhibitor
• HIF-1 alpha

Objectives: Before setting into the clinical trial using a combination of mammalian target of rapamycin (mTOR) inhibitors (rapamycin and everolimus) and other anticancer drugs, this study was conducted to confirm the efficacy of the new therapeutic strategy for ovarian clear cell adenocarcinoma (CCA), which targeted mTOR-hypoxia-induced factor (HIF) signal transduction system. %26lt;br%26gt;Materials and Methods: Using the cultured cells of CCA and animal models, alteration of mTOR-HIF cofactors and cell proliferation under the mTOR inhibitor-treated condition were analyzed. %26lt;br%26gt;Results: Mammalian target of rapamycin-HIF cofactors were inhibited dependent on concentration by mTOR inhibitor, resulting in suppression of the cultured CCA proliferation. However, von Hippel-Lindau was up-regulated at the messenger RNA level. In the nude mice with subcutaneously implanted CCA cells, apoptosis and necrosis were detected especially around the center of the tumors in the mTOR inhibitor-treated group more conspicuously than in the nontreated group. In the assessment of combination therapy with other antitumor agents, a combined treatment with mTOR inhibitor and chemotherapeutic agents caused a significant decrease in tumor size compared to the chemotherapeutic agents-only group. %26lt;br%26gt;Conclusions: Treatment by mTOR inhibitor is expected to down-regulate the cell proliferation of the CCA as a new therapeutic strategy.

• 出版日期2013-9