ArticleAnnals of surgical oncology2012
Novel C-terminal Hsp90 inhibitor for head and neck squamous cell cancer (HNSCC) with in vivo efficacy and improved toxicity profiles compared with standard agents.
Article in Annals of surgical oncology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 18 papers.
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18 citing papers in PubMed, 29 citations in OpenAlex.
- Review
- HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review).Oncology reports · 2023Review
- Article
- Synthesis and evaluation of 3'- and 4'-substituted cyclohexyl noviomimetics that modulate mitochondrial respiration.Bioorganic & medicinal chemistry · 2022Article
- Article
- Management of Hsp90-Dependent Protein Folding by Small Molecules Targeting the Aha1 Co-Chaperone.Cell chemical biology · 2020Article
- A novel heat shock protein 90 inhibitor potently targets adrenocortical carcinoma tumor suppression.Surgery · 2020Article
- Old and New Approaches to Target the Hsp90 Chaperone.Current cancer drug targets · 2020Review
- Mitochondrial-targeted Hsp90 C-terminal inhibitors manifest anti-proliferative activity.Bioorganic & medicinal chemistry letters · 2019Article
- Stimulation of heat shock protein 90 chaperone function through binding of a novobiocin analog KU-32.The Journal of biological chemistry · 2019Article
- Synthesis and evaluation of a ring-constrained Hsp90 C-terminal inhibitor that exhibits neuroprotective activity.Bioorganic & medicinal chemistry letters · 2018Article
- Novel C-Terminal Heat Shock Protein 90 Inhibitors (KU711 and Ku757) Are Effective in Targeting Head and Neck Squamous Cell Carcinoma Cancer Stem cells.Neoplasia (New York, N.Y.) · 2017Article
- Reduced Contractility and Motility of Prostatic Cancer-Associated Fibroblasts after Inhibition of Heat Shock Protein 90.Cancers · 2016Article
- Novobiocin Analogues That Inhibit the MAPK Pathway.Journal of medicinal chemistry · 2016Article
- Development of Noviomimetics as C-Terminal Hsp90 Inhibitors.ACS medicinal chemistry letters · 2016Article
- The novel HSP90 inhibitor AT13387 potentiates radiation effects in squamous cell carcinoma and adenocarcinoma cells.Oncotarget · 2015Article
- Novologues containing a benzamide side chain manifest anti-proliferative activity against two breast cancer cell lines.Bioorganic & medicinal chemistry letters · 2014Article
- Autophagic action of new targeting agents in head and neck oncology.Cancer biology & therapy · 2012Review
Corrections and comments
- Erratum issuedZhang, Xuan [added]
Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundCurrent therapies for HNSCC, especially platinum agents, are limited by their toxicities and drug resistance. This study evaluates a novel C-terminal Hsp90 inhibitor (CT-Hsp90-I) for efficacy and toxicity in vitro and in vivo in an orthotopic HNSCC model. Our hypothesis is that C-terminal inhibitors exhibit improved toxicity/efficacy profiles over standard therapies and may represent a novel group of anticancer agents.
methodsMDA-1986 HNSCC cells were treated with doses of 17-AAG or KU363 (a CT-Hsp90-I) and compared for antiproliferation by GLO-Titer and trypan blue exclusion and for apoptosis by PARP cleavage and caspase-3 inactivation by Western analysis. In vivo studies in Nu/Nu mice examined an orthotopic model of MDA-1986 cells followed by drug dosing intraperitoneally for a 21-day period (mg/kg/dose: cisplatin = 3.5, low-dose KU363 = 5, high-dose KU363 = 25, 17-AAG = 175). Tumor size, weight, and toxicity (body score) were measured 3×/week.
resultsThe IC(50) levels for KU363 = 1.2-2 μM in MDA-1986. KU363 induces apoptosis at 1 μM with cleavage of PARP and inactivation of caspase-3 levels after 24 h. Client proteins Akt and Raf-1 were also downregulated at 1-3 μM of drug. In vivo, 100% of controls had progressive disease, while 100% of cisplatin animals showed some response, all with significant systemic toxicity. High-dose KU363 showed 88% of animals responding and low-dose KU363 showed 75% responding. KU363 animals showed significantly less toxicity (P < 0.01) than cisplatin or 17-AAG.
conclusionThis novel CT-Hsp90-I KU363 manifests potent anticancer activity against HNSCC, showing excellent in vivo efficacy and reduced toxicity compared with standard agents justifying future translational evaluation.
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