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Pharmacokinetics and derivation of an anticancer dosing regimen for the novel anti-cancer agent isobutyl-deoxynyboquinone (IB-DNQ), a NQO1 bioactivatable molecule, in the domestic felid species

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Summary

Isobutyl-deoxynyboquinone (IB-DNQ) is a selective substrate for NAD(P)H:quinone oxidoreductase (NQO1), an enzyme overexpressed in many solid tumors. Following activation by NQO1, IB-DNQ participates in a catalytic futile reduction/reoxidation cycle with consequent toxic reactive oxygen species generation within the tumor microenvironment. To elucidate the potential of IB-DNQ to serve as a novel anticancer agent, in vitro studies coupled with in vivo pharmacokinetic and toxicologic investigations in the domestic felid species were conducted to investigate the tractability of IB-DNQ as a translationally applicable anticancer agent. First, using feline oral squamous cell carcinoma (OSCC) as a comparative cancer model, expressions of NQO1 were characterized in not only human, but also feline OSCC tissue microarrays. Second, IB-DNQ mediated cytotoxicity in three immortalized feline OSCC cell lines were studied under dose-dependent and sequential exposure conditions. Third, the feasibility of administering IB-DNQ at doses predicted to achieve cytotoxic plasma concentrations and biologically relevant durations of exposure were investigated through pharmacokinetic and tolerability studies in healthy research felines. Intravenous administration of IB-DNQ at 1.0–2.0 mg/kg achieved peak plasma concentrations and durations of exposure reaching or exceeding predicted in vitro cytotoxic concentrations. Clinical adverse side effects including ptyalism and tachypnea exhibited during and post-IV infusion of IB-DNQ were transient and tolerable. Additionally, IB-DNQ administration did not produce acute or delayed-onset unacceptable hematologic, non-hematologic, or off-target oxidative toxicities. Collectively, the findings reported here within provide important safety and pharmacokinetic data to support the continued development of IB-DNQ as a novel anticancer strategy for NQO1 expressing cancers.

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Acknowledgements

We thank the University of Illinois for support of this work. E.I.P. is a National Science Foundation and ACS Medicinal Chemistry predoctoral fellow.

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Authors and Affiliations

  1. Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, 61802, USA

    Alycen P. Lundberg, Malgorzata Pajak & Timothy M. Fan

  2. Carle R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Alycen P. Lundberg, Joshua M. Francis, Paul J. Hergenrother & Timothy M. Fan

  3. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Joshua M. Francis, Elizabeth I. Parkinson & Paul J. Hergenrother

  4. Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61802, USA

    Kathryn L. Wycislo

  5. Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210, USA

    Thomas J. Rosol & Cheryl A. London

  6. Department of Veterinary Clinical Sciences, The Ohio State University, Columbus, OH, 43210, USA

    Megan E. Brown

  7. Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, LA, 70803, USA

    Levent Dirikolu

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  1. Alycen P. Lundberg
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Correspondence to Timothy M. Fan.

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Conflict of interest

The University of Illinois has filed patents on DNQ and its derivatives including IB-DNQ with E.I.P. and P.J.H. listed as inventors.

Funding

We thank the University of Illinois for support of this work. E.I.P. is a National Science Foundation and ACS Medicinal Chemistry predoctoral fellow.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Electronic supplementary material

Supplemental Figure 1.

NQO1 antibody ab2346 at 1:1000. A549 is the human positive control, HEK293 is the human negative control, and SCCF1 is a feline oral squamous cell carcinoma. Bands are present for both at the expected protein product size and supports cross-reactivity of the antibody. (TIFF 1744 kb) (GIF 19 kb)

High resolution image (TIFF 1744 kb)

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Lundberg, A.P., Francis, J.M., Pajak, M. et al. Pharmacokinetics and derivation of an anticancer dosing regimen for the novel anti-cancer agent isobutyl-deoxynyboquinone (IB-DNQ), a NQO1 bioactivatable molecule, in the domestic felid species. Invest New Drugs 35, 134–144 (2017). https://doi.org/10.1007/s10637-016-0414-z

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