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dc.contributor.authorCohen, Stephanie M.
dc.contributor.authorMukerji, Ridhwi
dc.contributor.authorSamadi, Abbas K.
dc.contributor.authorZhao, Huiping
dc.contributor.authorBlagg, Brian S. J.
dc.contributor.authorCohen, Mark S.
dc.date.accessioned2018-04-27T17:21:00Z
dc.date.available2018-04-27T17:21:00Z
dc.date.issued2011-08-12
dc.identifier.citationCohen, S. M., Mukerji, R., Samadi, A. K., Zhao, H., Blagg, B. S. J., & Cohen, M. S. (2012). 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. Annals of Surgical Oncology, 19(Suppl 3), S483–S490. http://doi.org/10.1245/s10434-011-1971-1en_US
dc.identifier.urihttp://hdl.handle.net/1808/26385
dc.descriptionThe final publication is available at Springer via http://dx.doi.org/10.1245/s10434-011-1971-1.en_US
dc.description.abstractBackground - Current 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. Methods - MDA-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. Results - The IC50 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. Conclusion - This 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.en_US
dc.publisherSpringer Verlagen_US
dc.titleNovel C-Terminal Hsp90 Inhibitor for Head and Neck Squamous Cell Cancer (HNSCC) with in vivo Efficacy and Improved Toxicity Profiles Compared with Standard Agentsen_US
dc.typeArticleen_US
kusw.kudepartmentMedicinal Chemistryen_US
dc.identifier.doi10.1245/s10434-011-1971-1en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-0998-1496
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.rights.accessrightsopenAccessen_US


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