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: Kyung-Hun Lee, Ju-Hee Lee, Sae-Won Han, Seock-Ah Im, Tae-You Kim, Do-Youn Oh, Yung-Jue Bang
• Journal: Cancer science (Cancer Sci) Vol. 102 Issue 7 Pg. 1388-95 (Jul 2011) ISSN: 1349-7006 [Electronic] England
• PMID: 21453385 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Japanese Cancer Association.

Chemical References

• 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
• Antineoplastic Agents
• HSP70 Heat-Shock Proteins
• HSP90 Heat-Shock Proteins
• Isoxazoles
• Neoplasm Proteins
• Resorcinols
• Thymidylate Synthase
• ERBB2 protein, human
• Receptor, ErbB-2
• Proteasome Endopeptidase Complex

Topics

• Antineoplastic Agents (pharmacology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Drug Synergism
• HSP70 Heat-Shock Proteins (biosynthesis)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Isoxazoles (pharmacology)
• Neoplasm Proteins (metabolism)
• Proteasome Endopeptidase Complex (physiology)
• Receptor, ErbB-2 (metabolism)
• Resorcinols (pharmacology)
• Stomach Neoplasms (drug therapy, pathology)
• Thymidylate Synthase (antagonists & inhibitors)