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Investigational New Drugs

, Volume 35, Issue 2, pp 134–144 | Cite as

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

  • Alycen P. Lundberg
  • Joshua M. Francis
  • Malgorzata Pajak
  • Elizabeth I. Parkinson
  • Kathryn L. Wycislo
  • Thomas J. Rosol
  • Megan E. Brown
  • Cheryl A. London
  • Levent Dirikolu
  • Paul J. Hergenrother
  • Timothy M. FanEmail author
PRECLINICAL STUDIES

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.

Keywords

NQO1 Deoxynyboquinone β-lapachone Feline oral squamous cell carcinoma Novel anti-cancer agent Comparative oncology 

Notes

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.

Compliance with ethical standards

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.

Informed consent

Not applicable.

Supplementary material

10637_2016_414_Fig6_ESM.gif (19 kb)
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)

10637_2016_414_MOESM1_ESM.tif (1.7 mb)
High resolution image (TIFF 1744 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Alycen P. Lundberg
    • 1
    • 2
  • Joshua M. Francis
    • 2
    • 3
  • Malgorzata Pajak
    • 1
  • Elizabeth I. Parkinson
    • 3
  • Kathryn L. Wycislo
    • 4
  • Thomas J. Rosol
    • 5
  • Megan E. Brown
    • 6
  • Cheryl A. London
    • 5
  • Levent Dirikolu
    • 7
  • Paul J. Hergenrother
    • 2
    • 3
  • Timothy M. Fan
    • 1
    • 2
    Email author
  1. 1.Department of Veterinary Clinical MedicineUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  2. 2.Carle R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to PeopleUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  3. 3.Department of ChemistryUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  4. 4.Department of PathobiologyUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  5. 5.Department of Veterinary BiosciencesThe Ohio State UniversityColumbusUSA
  6. 6.Department of Veterinary Clinical SciencesThe Ohio State UniversityColumbusUSA
  7. 7.Department of Comparative Biomedical SciencesLouisiana State UniversityBaton RougeUSA

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