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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

  • Translational Research and Biomarkers
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Annals of Surgical Oncology Aims and scope Submit manuscript

An Erratum to this article was published on 07 March 2012

Abstract

Background

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.

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Acknowledgment

The authors would like to acknowledge grant support for this project from NIH 2U01-CA-120458-04 (B.S.J. Blagg and M.S. Cohen).

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Authors and Affiliations

  1. Department of Surgery, University of Kansas Medical Center, Kansas City, KS, USA

    Stephanie M. Cohen MD, Ridhwi Mukerji MD, Abbas K. Samadi PhD & Mark S. Cohen MD, FACS

  2. Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA

    Huiping Zhao PhD & Brian S. J. Blagg PhD

Authors
  1. Stephanie M. Cohen MD
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  2. Ridhwi Mukerji MD
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  3. Abbas K. Samadi PhD
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  4. Huiping Zhao PhD
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  5. Brian S. J. Blagg PhD
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  6. Mark S. Cohen MD, FACS
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Corresponding author

Correspondence to Stephanie M. Cohen MD.

Additional information

Stephanie M. Cohen and Ridhwi Mukerji are co-first authors.

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Cohen, S.M., Mukerji, R., Samadi, A.K. et al. 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. Ann Surg Oncol 19 (Suppl 3), 483–490 (2012). https://doi.org/10.1245/s10434-011-1971-1

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  • DOI: https://doi.org/10.1245/s10434-011-1971-1

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