title: The Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin increases cisplatin antitumor activity by inducing p53-mediated apoptosis in head and neck cancer.
abstract: The tumor suppressor p53 is often inactivated in head and neck cancer (HNC) through TP53 mutations or overexpression of mouse double minute 2 or mouse double minute X. Restoration of p53 function by counteracting these p53 repressors is a promising strategy for cancer treatment. The present study assessed the ability of a heat shock protein 90 (Hsp90) inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), to induce apoptosis in HNC by restoring p53 function. The effect of 17AAG, alone or in combination with Nutlin-3a or cisplatin, was assessed in HNC cells using growth and apoptosis, immunoblotting, quantitative reverse transcription-polymerase chain reaction, and preclinical tumor xenograft models. 17AAG activated and stabilized p53 in HNC cells bearing wild-type TP53 by disrupting the p53-MDMX interaction. 17AAG upregulated p21 and proapoptotic gene expression, and promoted apoptosis in a concentration-dependent manner. Growth inhibition by 17AAG was highest in tumor cells with MDMX overexpression. The apoptotic response was blocked by inhibition of p53 expression, demonstrating that the effect of 17AAG depended on p53 and MDMX. 17AAG synergized in vitro with Nutlin-3a and in vitro and in vivo with cisplatin to induce p53-mediated apoptosis. 17AAG effectively induced p53-mediated apoptosis in HNC cells through MDMX inhibition and increased the antitumor activity of cisplatin synergistically, suggesting a promising strategy for treating HNC.
authors: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: J-L
authors: JL
authors: Roh
authors: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: E H
authors: EH
authors: Kim
authors: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: H B
authors: HB
authors: Park
authors: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: J Y
authors: JY
authors: Park
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000627:therapeutic use*; D015153:Blotting, Western; D002460:Cell Line; D002945:Cisplatin / Q000627:therapeutic use*; D003513:Cycloheximide / Q000627:therapeutic use*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C112765:tanespimycin; D003513:Cycloheximide; D002945:Cisplatin