title: Antitumor activity of NVP-AUY922, a novel heat shock protein 90 inhibitor, in human gastric cancer cells is mediated through proteasomal degradation of client proteins.
abstract: Heat shock protein 90 (HSP90) is a molecular chaperone required for the stability of key regulators of cell survival and is an emerging target of cancer therapy. NVP-AUY922, a novel and potent inhibitor of HSP90, was evaluated against gastric cancer cell lines. NVP-AUY922 significantly inhibited the proliferation of all tested gastric cancer cell lines with 50% inhibitory concentration in the range of 2-40 nM and potently induced the degradation of growth factor receptors and other client proteins including HER-2, Akt and thymidylate synthase. HSP70 was induced by NVP-AUY922 and its binding with client proteins led to their proteasomal degradation. Moreover, the combination of NVP-AUY922 with cytotoxic chemotherapeutic agents such as 5-fluorouracil and oxaliplatin created a synergistic effect. Taken together, these preclinical data demonstrate the potent activity of NVP-AUY922 against gastric cancer cells and offer a rationale for clinical development of the agent alone or in combination with other chemotherapeutic drugs to effectively treat gastric cancer.
authors: Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
authors: Kyung-Hun
authors: KH
authors: Lee
authors: Ju-Hee
authors: JH
authors: Lee
authors: Sae-Won
authors: SW
authors: Han
authors: Seock-Ah
authors: SA
authors: Im
authors: Tae-You
authors: TY
authors: Kim
authors: Do-Youn
authors: DY
authors: Oh
authors: Yung-Jue
authors: YJ
authors: Bang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D009363:Neoplasm Proteins; D046988:Proteasome Endopeptidase Complex; D018719:Erb-b2 Receptor Tyrosine Kinases; D012118:Resorcinols; D013940:Thymidylate Synthase; C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; C508053:ERBB2 protein, human