Article

Tumor Selectivity of Hsp90 Inhibitors: The Explanation Remains Elusive

Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
ACS Chemical Biology (Impact Factor: 5.33). 07/2006; 1(5):279-84. DOI: 10.1021/cb600224w
Source: PubMed

ABSTRACT

Two recent papers attempt to solve both the tumor selectivity and the in vivo tumor accumulation profiles seen with some Hsp90 inhibitors. They spotlight the higher affinity of ansamycins' hydroquinone over the quinone form for Hsp90 and further discuss its possible contribution to ansamycins' tumor selectivity.

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    • "Emerging clinical data identify Hsp90 inhibition as a promising therapeutic strategy to treat cancer (Neckers and Trepel, 2014). Cancer cells appear to be particularly sensitive to Hsp90 inhibitors compared to non-transformed cells (Chiosis and Neckers, 2006), and Hsp90 inhibitors are retained by tumors in vivo far longer than in normal tissues (Kamal et al., 2003). However, the molecular basis of these phenomena remains undefined. "
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    ABSTRACT: The molecular chaperone Hsp90 protects deregulated signaling proteins that are vital for tumor growth and survival. Tumors generally display sensitivity and selectivity toward Hsp90 inhibitors; however, the molecular mechanism underlying this phenotype remains undefined. We report that the mitotic checkpoint kinase Mps1 phosphorylates a conserved threonine residue in the amino-domain of Hsp90. This, in turn, regulates chaperone function by reducing Hsp90 ATPase activity while fostering Hsp90 association with kinase clients, including Mps1. Phosphorylation of Hsp90 is also essential for the mitotic checkpoint because it confers Mps1 stability and activity. We identified Cdc14 as the phosphatase that dephosphorylates Hsp90 and disrupts its interaction with Mps1. This causes Mps1 degradation, thus providing a mechanism for its inactivation. Finally, Hsp90 phosphorylation sensitizes cells to its inhibitors, and elevated Mps1 levels confer renal cell carcinoma selectivity to Hsp90 drugs. Mps1 expression level can potentially serve as a predictive indicator of tumor response to Hsp90 inhibitors.
    Full-text · Article · Jan 2016 · Cell Reports
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    • "Hsp90 inhibitors exert the antitumor effect by blocking the ATP binding domain of Hsp90 to abolish the Hsp90 chaperone function and leading to proteasomal degradation of the oncogenic client proteins. In tumor cells, the dependency of oncoproteins on the chaperone function of Hsp90 is much higher than in normal cells, and the binding affinity of Hsp90 inhibitor to Hsp90 was 100-fold higher in tumor cells than in normal cells [9-11]. For this reason, inhibition of the Hsp90 machinery is considered as a potent strategy in cancer therapies [12]. "
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    ABSTRACT: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy strongly associated with Epstein-Barr virus (EBV). AT13387 is a novel heat shock protein 90 (Hsp90) inhibitor, which inhibits the chaperone function of Hsp90 and reduces expression of Hsp90-dependent client oncoproteins. This study aimed to evaluate both the in vitro and in vivo antitumor effects of AT13387 in the EBV-positive NPC cell line C666-1. Our results showed that AT13387 inhibited C666-1 cell growth and induced cellular senescence with the downregulation of multiple Hsp90 client oncoproteins EGFR, AKT, CDK4, and restored the protein expression of negative cell cycle regulator p27. We also studied the ability of AT13387 to restore p27 expression by downregulation of AKT and the p27 ubiquitin mediator, Skp2, using AKT inhibitor and Skp2 siRNA. In the functional study, AT13387 inhibited cell migration with downregulation of a cell migration regulator, HDAC6, and increased the acetylation and stabilization of alpha-tubulin. We also examined the effect of AT13387 on putative cancer stem cells (CSC) by 3-D tumor sphere formation assay. AT13387 effectively reduced both the number and size of C666-1 tumor spheres with decreased expression of NPC CSC-like markers CD44 and SOX2. In the in vivo study, AT13387 significantly suppressed tumor formation in C666-1 NPC xenografts. AT13387 suppressed cell growth, cell migration, tumor sphere formation and induced cellular senescence on EBV-positive NPC cell line C666-1. Also, the antitumor effect of AT13387 was demonstrated in an in vivo model. This study provided experimental evidence for the preclinical value of using AT13387 as an effective antitumor agent in treatment of NPC.
    Full-text · Article · Oct 2013 · Molecular Cancer
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    • "A heat shock protein (HSP) is a molecular chaperone that refolds damaged proteins in the cell [1,2]. Protein refolding is responsible for cell survival under stressed conditions, and most cancer cells take advantage of the HSP-mediated cell protection machinery by overexpressing HSPs [3]. "
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    ABSTRACT: Cross-linked nanoassemblies (CNAs) with a degradable core were prepared for sustained release of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), a potent inhibitor of heat shock protein 90 (HSP90). The particle size of CNAs ranged between 100 and 250 nm, which changed depending on the cross-linking yields and drug entrapment method. CNAs with a 1% cross-linking yield entrapped 17-AAG in aqueous solutions, yet degraded in 3 hrs. CNAs entrapped 5.2 weight% of 17-AAG as the cross-linking yield increased to 10%, retaining more than 80% of particles for 24 hrs. CNAs with drugs entrapped after the cross-linking reactions were 100 nm and remained stable in both pH 7.4 and 5.0, corresponding to the physiological, tumoral, and intracellular environments. Drug was completely released from CNAs in 48 hrs, which would potentially maximize drug delivery and release efficiency within tumor tissues. Drug release patterns were not negatively affected by changing the cross-linking yields of CNAs. CNAs entrapping 17-AAG suppressed the growth of human non-small cell lung cancer A549 cells as equally effective as free drugs. The results demonstrated that CNAs would be a promising formulation that can be used in aqueous solutions for controlled delivery and release of 17-AAG.
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