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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.

AbstractOBJECTIVES:
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.
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.
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.
CONCLUSIONS:
Treatment by mTOR inhibitor is expected to down-regulate the cell proliferation of the CCA as a new therapeutic strategy.
AuthorsTakeshi Hirasawa, Masaki Miyazawa, Masanori Yasuda, Masako Shida, Masae Ikeda, Hiroshi Kajiwara, Naruaki Matsui, Mariko Fujita, Toshinari Muramatsu, Mikio Mikami
JournalInternational journal of gynecological cancer : official journal of the International Gynecological Cancer Society (Int J Gynecol Cancer) Vol. 23 Issue 7 Pg. 1210-8 (Sep 2013) ISSN: 1525-1438 [Electronic] England
PMID23899586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibiotics, Antineoplastic
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunosuppressive Agents
  • RNA, Messenger
  • Everolimus
  • Von Hippel-Lindau Tumor Suppressor Protein
  • MTOR protein, human
  • Oncogene Protein v-akt
  • TOR Serine-Threonine Kinases
  • VHL protein, human
  • Sirolimus
Topics
  • Adenocarcinoma, Clear Cell (drug therapy, metabolism, mortality, pathology)
  • Animals
  • Antibiotics, Antineoplastic (pharmacology)
  • Apoptosis (drug effects)
  • Blotting, Western
  • Cell Proliferation (drug effects)
  • Drug Therapy, Combination
  • Everolimus
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
  • Immunoenzyme Techniques
  • Immunosuppressive Agents (pharmacology)
  • In Vitro Techniques
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Oncogene Protein v-akt (genetics, metabolism)
  • Ovarian Neoplasms (drug therapy, metabolism, mortality, pathology)
  • Prognosis
  • RNA, Messenger (genetics)
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction (drug effects)
  • Sirolimus (analogs & derivatives, pharmacology)
  • Survival Rate
  • TOR Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
  • Tumor Cells, Cultured
  • Von Hippel-Lindau Tumor Suppressor Protein (genetics, metabolism)
  • Xenograft Model Antitumor Assays

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