Antitumor effect of novel HSP90 inhibitor NVP-AUY922 against oral squamous cell carcinoma (original) (raw)
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The Therapeutic Target Hsp90 and Cancer Hallmarks
Current Pharmaceutical Design, 2012
Hsp90 is a major molecular chaperone that is expressed abundantly and plays a pivotal role in assisting correct folding and functionality of its client proteins in cells. The Hsp90 client proteins include a wide variety of signal transducing molecules such as protein kinases and steroid hormone receptors. Cancer is a complex disease, but most types of human cancer share common hallmarks, including self-sufficiency in growth signals, insensitivity to growth-inhibitory mechanism, evasion of programmed cell death, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. A surprisingly large number of Hsp90-client proteins play crucial roles in establishing cancer cell hallmarks. We start the review by describing the structure and function of Hsp90 since conformational changes during the ATPase cycle of Hsp90 are closely related to its function. Many co-chaperones, including Hop, p23, Cdc37, Aha1, and PP5, work together with Hsp90 by modulating the chaperone machinery. Post-translational modifications of Hsp90 and its co-chaperones are vital for their function. Many tumor-related Hsp90-client proteins, including signaling kinases, steroid hormone receptors, p53, and telomerase, are described. Hsp90 and its co-chaperones are required for the function of these tumor-promoting client proteins; therefore, inhibition of Hsp90 by specific inhibitors such as geldanamycin and its derivatives attenuates the tumor progression. Hsp90 inhibitors can be potential and effective cancer chemotherapeutic drugs with a unique profile and have been examined in clinical trials. We describe possible mechanisms why Hsp90 inhibitors show selectivity to cancer cells even though Hsp90 is essential also for normal cells. Finally, we discuss the "Hsp90-addiction" of cancer cells, and suggest a role for Hsp90 in tumor evolution.
Effectiveness of Hsp90 Inhibitors as Anti-Cancer Drugs
Mini-Reviews in Medicinal Chemistry, 2006
Hsp90 is a chaperone with over 100 identified client proteins. What makes Hsp90 especially promising as a target for anti-cancer drugs is that many of its client proteins are in signaling and chromatin-remodeling pathways, and these pathways are often disrupted in many types of cancers. Recently, it was determined that Hsp90 bound to a client protein in a co-chaperone complex has a higher ATPase activity and binds to the geldanamycin inhibitor with over 100fold higher affinity than the low-ATPase form. Consequently, despite Hsp90 being an abundant protein in most cell types, Hsp90 inhibitors accumulate at high levels primarily in tumor cells because tumor cells are "oncogene addicted" and require especially high levels of the high-ATPase form of Hsp90. Numerous classes of Hsp90 inhibitors have recently been developed, such as the anasamysin geldanamycin and derivatives 17-AAG and 17-DMAG; the macrolide radicicol and derivatives; purine-scaffold derivatives; pyrazoles; and shepherdins that bind to the N-terminal high-affinity ATP-binding domain of Hsp90. Other inhibitors have recently been shown to bind to the C-terminal dimerization domain of Hsp90, such as cisplatin and novobiocin, or modify Hsp90 postranslationally, such as histone deacetylase or proteasome inhibitors. In this mini-review, we present hypothetical mechanisms for Hsp90 inhibitors in treating cancers, preliminary studies in early clinical trials, and potential tumor-killing and tumor-promoting activities of Hsp90 inhibitors.
Cancer Research, 2008
We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (K d = 1.7 nmol/L) and proliferation of human tumor cells with GI 50 values of approximately 2 to 40 nmol/L, inducing G 1 -G 2 arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI 50 . This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1A, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro , WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials. [Cancer Res 2008;68(8):2850-60]
The HSP90 Inhibitor NVP-AUY922 Potently Inhibits Non–Small Cell Lung Cancer Growth
Molecular Cancer Therapeutics, 2013
Heat shock protein 90 (HSP90) is involved in protein folding and functions as a chaperone for numerous client proteins, many of which are important in non–small cell lung cancer (NSCLC) pathogenesis. We sought to define preclinical effects of the HSP90 inhibitor NVP-AUY922 and identify predictors of response. We assessed in vitro effects of NVP-AUY922 on proliferation and protein expression in NSCLC cell lines. We evaluated gene expression changes induced by NVP-AUY922 exposure. Xenograft models were evaluated for tumor control and biological effects. NVP-AUY922 potently inhibited in vitro growth in all 41 NSCLC cell lines evaluated with IC50 < 100 nmol/L. IC100 (complete inhibition of proliferation) < 40 nmol/L was seen in 36 of 41 lines. Consistent gene expression changes after NVP-AUY922 exposure involved a wide range of cellular functions, including consistently decreased dihydrofolate reductase after exposure. NVP-AUY922 slowed growth of A549 (KRAS-mutant) xenografts and ...
Molecular basis for the actions of Hsp90 inhibitors and cancer therapy
The Journal of Antibiotics, 2011
Heat-shock protein 90 (Hsp90) inhibitor downregulates c-Myc expression and upregulates the expression of tumor repressor proteins such as p53 and pRB, inhibiting the G1/S transition and causing G2/M arrest during cell cycle progression. The cycle progression is extensively controlled by the pRB/E2F signaling pathway. E2F is released from the pRB/E2F complex with the phosphorylation of pRB by cyclin-cyclin-dependent kinase (CDK) complexes. The released E2F promotes the transcription of target genes involved in cell cycle progression. The pRB/E2F signaling pathway is controlled by DNA methyltransferase-1 (Dnmt-1). The elevated expression of Dnmt-1 has been reported in carcinomas of the colon, lung and prostate. A defect of pRB expression in RbÀ/À cancer cells is caused by the aberrant methylation of CpG in the Rb promoter. The Hsp90 inhibitor disrupts the Dnmt-1/Hsp90 association and upregulates pRB expression. In this review, the Hsp90 inhibitors that show promise for cancer therapy are summarized.
Cancer Investigation, 2020
Heat shock protein 90 (HSP90), a highly and unique chaperone, presents as a double-edged sword. It plays an essential role in many physiological and pathological processes, including tumor development. The current review highlights a recent understanding of the roles of HSP90 in molecular mechanisms underlying cancer survival and progression. HSP90 and its client proteins through the regulation of oncoproteins including signaling proteins, receptors and transcriptional factors involved in tumorigenesis. It also has potential clinical application as diagnostic and prognostic biomarkers for assessing cancer progression. In this way, using HSP90 to develop new anti-cancer therapeutic agents including HSP90 inhibitors, anti-HSP90 antibody, and HSP90-based vaccines has been promising.
Oncology Reports, 2012
Heat shock protein 90 (HSP90), a molecular chaperone, has provoked great interest as a promising molecular target for cancer treatment, due to its involvement in regulating the conformation, stability and functions of key oncogenic proteins. At present, a variety of chemical compounds targeting HSP90 have been developed and have shown convincing anti-neoplastic activity in various preclinical tumor models. The aim of our study was to evaluate the antitumor effects of a novel HSP90 inhibitor, NVP-AUY922, in esophageal squamous cancer cells (ESCC). Four ESCC cell lines (TE-1, TE-4, TE-8, TE-10) were examined. NVP-AUY922 potently inhibited the proliferation of ESCC, particularly in PTEN-null TE-4 cells with a 2-3 times lower IC 50 than the other three cell lines. Western blot analysis showed that PTEN-null TE-4 cells exhibited higher AKT and ERK activity, which contribute to cell proliferation and survival. NVP-AUY922 significantly suppressed the activity of AKT and ERK in TE-4 but not in PTEN-proficient TE-10 cells. Genetic modification experiments demonstrated that the sensitivity to NVP-AUY922 was decreased by exogenous transduction of PTEN in TE-4 and increased by silencing PTEN expression in intact PTEN-expressing TE-10, suggesting that the expression of PTEN may be associated with cell sensitivity in HSP90 inhibition. Furthermore, the enhanced activity of AKT in PTENsilenced TE-10 was more easily suppressed by NVP-AUY922. Collectively, NVP-AUY922 exhibits a strong antiproliferative effect, revealing its potential as a novel therapeutic alternative to current ESCC treatment. The effect may be improved further by impeding PTEN expression.