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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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References

  1. Pavet V, Portal MM, Moulin JC, Herbrecht R, Gronemeyer H (2011) Towards novel paradigms for cancer therapy. Oncogene 30(1):1–20

    Article  CAS  PubMed  Google Scholar 

  2. Kundu SK, Nestor M (2012) Targeted therapy in head and neck cancer. Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine 33(3):707–721

    Article  CAS  Google Scholar 

  3. Pink JJ, Planchon SM, Tagliarino C, Varnes ME, Siegel D, Boothman DA (2000) NAD(P)H:Quinone oxidoreductase activity is the principal determinant of beta-lapachone cytotoxicity. J Biol Chem 275(8):5416–5424

    Article  CAS  PubMed  Google Scholar 

  4. Danson S, Ward TH, Butler J, Ranson M (2004) DT-diaphorase: a target for new anticancer drugs. Cancer Treat Rev 30(5):437–449

    Article  CAS  PubMed  Google Scholar 

  5. Siegel D, Yan C, Ross D (2012) NAD(P)H:quinone oxidoreductase 1 (NQO1) in the sensitivity and resistance to antitumor quinones. Biochem Pharmacol 83(8):1033–1040

    Article  CAS  PubMed  Google Scholar 

  6. Parkinson EI, Hergenrother PJ (2015) Deoxynyboquinones as NQO1-activated cancer therapeutics. Acc Chem Res 48(10):2715–2723

    Article  CAS  PubMed  Google Scholar 

  7. Schlager JJ, Powis G (1990) Cytosolic NAD(P)H:(quinone-acceptor) oxidoreductase in human normal and tumor tissue: effects of cigarette smoking and alcohol. Int J Cancer 45(3):403–409

    Article  CAS  PubMed  Google Scholar 

  8. Malkinson AM, Siegel D, Forrest GL, Gazdar AF, Oie HK, Chan DC, Bunn PA, Mabry M, Dykes DJ, Harrison SD et al (1992) Elevated DT-diaphorase activity and messenger RNA content in human non-small cell lung carcinoma: relationship to the response of lung tumor xenografts to mitomycin Cl. Cancer Res 52(17):4752–4757

    CAS  PubMed  Google Scholar 

  9. Smitskamp-Wilms E, Giaccone G, Pinedo HM, van der Laan BF, Peters GJ (1995) DT-diaphorase activity in normal and neoplastic human tissues; an indicator for sensitivity to bioreductive agents? Br J Cancer 72(4):917–921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Marin A, de Lopez Cerain A, Hamilton E, Lewis AD, Martinez-Penuela JM, Idoate MA, Bello J (1997) DT-diaphorase and cytochrome B5 reductase in human lung and breast tumours. Br J Cancer 76(7):923–929

    Article  CAS  PubMed  Google Scholar 

  11. Siegel D, Ross D (2000) Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues. Free Radic Biol Med 29(3–4):246–253

    Article  CAS  PubMed  Google Scholar 

  12. Kolesar JM, Pritchard SC, Kerr KM, Kim K, Nicolson MC, McLeod H (2002) Evaluation of NQO1 gene expression and variant allele in human NSCLC tumors and matched normal lung tissue. Int J Oncol 21(5):1119–1124

    CAS  PubMed  Google Scholar 

  13. Bey EA, Bentle MS, Reinicke KE, Dong Y, Yang CR, Girard L, Minna JD, Bornmann WG, Gao J, Boothman DA (2007) An NQO1- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone. Proc Natl Acad Sci U S A 104(28):11832–11837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Li Z, Zhang Y, Jin T, Men J, Lin Z, Qi P, Piao Y, Yan G (2015) NQO1 protein expression predicts poor prognosis of non-small cell lung cancers. BMC Cancer 15:207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Logsdon CD, Simeone DM, Binkley C, Arumugam T, Greenson JK, Giordano TJ, Misek DE, Kuick R, Hanash S (2003) Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer. Cancer Res 63(10):2649–2657

    CAS  PubMed  Google Scholar 

  16. Lewis AM, Ough M, Hinkhouse MM, Tsao MS, Oberley LW, Cullen JJ (2005) Targeting NAD(P)H:quinone oxidoreductase (NQO1) in pancreatic cancer. Mol Carcinog 43(4):215–224

    Article  CAS  PubMed  Google Scholar 

  17. Lyn-Cook BD, Yan-Sanders Y, Moore S, Taylor S, Word B, Hammons GJ (2006) Increased levels of NAD(P)H: quinone oxidoreductase 1 (NQO1) in pancreatic tissues from smokers and pancreatic adenocarcinomas: a potential biomarker of early damage in the pancreas. Cell Biol Toxicol 22(2):73–80

    Article  CAS  PubMed  Google Scholar 

  18. Li LS, Reddy S, Lin ZH, Liu S, Park H, Chun SG, Bornmann WG, Thibodeaux J, Yan J, Chakrabarti G et al (2016) NQO1-mediated tumor-selective lethality and Radiosensitization for head and neck cancer. Mol Cancer Ther 15(7):1757–1767

    Article  CAS  PubMed  Google Scholar 

  19. Parkinson EI, Bair JS, Cismesia M, Hergenrother PJ (2013) Efficient NQO1 substrates are potent and selective anticancer agents. ACS Chem Biol 8(10):2173–2183

    Article  CAS  PubMed  Google Scholar 

  20. Park HJ, Ahn KJ, Ahn SD, Choi E, Lee SW, Williams B, Kim EJ, Griffin R, Bey EA, Bornmann WG et al (2005) Susceptibility of cancer cells to beta-lapachone is enhanced by ionizing radiation. Int J Radiat Oncol Biol Phys 61(1):212–219

    Article  CAS  PubMed  Google Scholar 

  21. Terai K, Dong GZ, Oh ET, Park MT, Gu Y, Song CW, Park HJ (2009) Cisplatin enhances the anticancer effect of beta-lapachone by upregulating NQO1. Anti-Cancer Drugs 20(10):901–909

    Article  CAS  PubMed  Google Scholar 

  22. Ahn KJ, Lee HS, Bai SK, Song CW (2013) Enhancement of radiation effect using beta-lapachone and underlying mechanism. Radiation Oncology Journal 31(2):57–65

    Article  PubMed  PubMed Central  Google Scholar 

  23. Bermejo M, Mangas-Sanjuan V, Gonzalez-Alvarez I, Gonzalez-Alvarez M (2016) Enhancing oral absorption of beta-lapachone: progress till date. Eur J Drug Metab Pharmacokinet. doi:10.1007/s13318-016-0369-7

  24. Blanco E, Bey EA, Dong Y, Weinberg BD, Sutton DM, Boothman DA, Gao J (2007) Beta-lapachone-containing PEG-PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells. Journal of Controlled Release: Official Journal of the Controlled Release Society 122(3):365–374

    Article  CAS  Google Scholar 

  25. Blanco E, Bey EA, Khemtong C, Yang SG, Setti-Guthi J, Chen H, Kessinger CW, Carnevale KA, Bornmann WG, Boothman DA et al (2010) Beta-lapachone micellar nanotherapeutics for non-small cell lung cancer therapy. Cancer Res 70(10):3896–3904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ma X, Huang X, Moore Z, Huang G, Kilgore JA, Wang Y, Hammer S, Williams NS, Boothman DA, Gao J (2015) Esterase-activatable beta-lapachone prodrug micelles for NQO1-targeted lung cancer therapy. Journal of Controlled Release: Official Journal of the Controlled Release Society 200:201–211

    Article  CAS  Google Scholar 

  27. Zhang L, Chen Z, Yang K, Liu C, Gao J, Qian F (2015) Beta-lapachone and paclitaxel combination micelles with improved drug encapsulation and therapeutic synergy as novel nanotherapeutics for NQO1-targeted cancer therapy. Mol Pharm 12(11):3999–4010

    Article  CAS  PubMed  Google Scholar 

  28. Bair JS, Palchaudhuri R, Hergenrother PJ (2010) Chemistry and biology of deoxynyboquinone, a potent inducer of cancer cell death. J Am Chem Soc 132(15):5469–5478

    Article  CAS  PubMed  Google Scholar 

  29. Mak IW, Evaniew N, Ghert M (2014) Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res 6(2):114–118

    PubMed  PubMed Central  Google Scholar 

  30. Kamb A (2005) What's wrong with our cancer models? Nat Rev Drug Discov 4(2):161–165

    Article  CAS  PubMed  Google Scholar 

  31. Talmadge JE, Singh RK, Fidler IJ, Raz A (2007) Murine models to evaluate novel and conventional therapeutic strategies for cancer. Am J Pathol 170(3):793–804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172(5):2731–2738

    Article  CAS  PubMed  Google Scholar 

  33. Richmond A, Su Y (2008) Mouse xenograft models vs GEM models for human cancer therapeutics. Disease Models & Mechanisms 1(2–3):78–82

    Article  Google Scholar 

  34. Khanna C, Lindblad-Toh K, Vail D, London C, Bergman P, Barber L, Breen M, Kitchell B, McNeil E, Modiano JF et al (2006) The dog as a cancer model. Nat Biotechnol 24(9):1065–1066

    Article  CAS  PubMed  Google Scholar 

  35. Paoloni M, Khanna C (2008) Translation of new cancer treatments from pet dogs to humans. Nat Rev Cancer 8(2):147–156

    Article  CAS  PubMed  Google Scholar 

  36. LeBlanc AK, Breen M, Choyke P, Dewhirst M, Fan TM, Gustafson DL, Helman LJ, Kastan MB, Knapp DW, Levin WJ et al (2016) Perspectives from man's best friend: National Academy of Medicine's workshop on comparative oncology. Sci Transl Med 8(324):324ps5

    Article  PubMed  Google Scholar 

  37. Paoloni M, Davis S, Lana S, Withrow S, Sangiorgi L, Picci P, Hewitt S, Triche T, Meltzer P, Khanna C (2009) Canine tumor cross-species genomics uncovers targets linked to osteosarcoma progression. BMC Genomics 10:625

    Article  PubMed  PubMed Central  Google Scholar 

  38. Angstadt AY, Motsinger-Reif A, Thomas R, Kisseberth WC, Guillermo Couto C, Duval DL, Nielsen DM, Modiano JF, Breen M (2011) Characterization of canine osteosarcoma by array comparative genomic hybridization and RT-qPCR: signatures of genomic imbalance in canine osteosarcoma parallel the human counterpart. Genes Chromosom Cancer 50(11):859–874

    Article  CAS  PubMed  Google Scholar 

  39. Breen M, Modiano JF (2008) Evolutionarily conserved cytogenetic changes in hematological malignancies of dogs and humans--man and his best friend share more than companionship. Chromosome Research: an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology 16(1):145–154

    Article  CAS  Google Scholar 

  40. Wypij JM (2013) A naturally occurring feline model of head and neck squamous cell carcinoma. Pathol Res Int 2013:502197

    Article  Google Scholar 

  41. Supsavhad W, Dirksen WP, Martin CK, Rosol TJ (2016) Animal models of head and neck squamous cell carcinoma. Vet J 210:7–16

    Article  PubMed  Google Scholar 

  42. Bilgic O, Duda L, Sanchez MD, Lewis JR (2015) Feline oral squamous cell carcinoma: clinical manifestations and literature review. J Vet Dent 32(1):30–40

    Article  PubMed  Google Scholar 

  43. Stebbins KE, Morse CC, Goldschmidt MH (1989) Feline oral neoplasia: a ten-year survey. Vet Pathol 26(2):121–128

    Article  CAS  PubMed  Google Scholar 

  44. Vichai V, Kirtikara K (2006) Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 1(3):1112–1116

    Article  CAS  PubMed  Google Scholar 

  45. Parkinson EI, Hergenrother PJ (2011) Runaway ROS as a selective anticancer strategy. Chem Med Chem 6(11):1957–1959

  46. Huang X, Dong Y, Bey EA, Kilgore JA, Bair JS, Li LS, Patel M, Parkinson EI, Wang Y, Williams NS et al (2012) An NQO1 substrate with potent antitumor activity that selectively kills by PARP1-induced programmed necrosis. Cancer Res 72(12):3038–3047

  47. Court MH (2013) Feline drug metabolism and disposition: pharmacokinetic evidence for species differences and molecular mechanisms. Vet Clin North Am Small Anim Pract 43(5):1039–1054

  48. Booth DM (1990) Drug therapy in cats: mechanisms and avoidance of adverse drug reactions. J Am Vet Med Assoc 196(8):1297–1305

  49. Hill AS, O'Neill S, Rogers QR, Christopher MM (2001) Antioxidant prevention of Heinz body formation and oxidative injury in cats. Am J Vet Res 62(3):370–37

  50. Yang Y, Zhang Y, Wu Q, Cui X, Lin Z, Liu S, Chen L (2014) Clinical implications of high NQO1 expression in breast cancers. J Exp Clin Cancer Res 33:14

  51. Lin L, Quin Y, Jin T, Liu S, Zhang S, Shen X, Lin Z (2014) Significance of NQO1 overexpression for prognostic evaluation of gastric adenocarcinoma. Exp Mol Pathol 96(2):200–205

  52. Cui X, Jin T, Wang X, Jin G, Li Z, Lin L (2014) NAD(P)H:quinone oxideoreductase-1 overexpression predicts poor prognosis in small cell lung cancer. Oncol Rep 32(6):2589–2595

  53. Ma Y, Kong J, Yan G, Ren X, Jin D, Jin T, Lin L, Lin Z (2014) NQO1 overexpression is associated with poor prognosis in squamous cell carcinoma of the uterine cervix. BMC Cancer 14:414

  54. Li LS, Bey EA, Dong Y, Meng J, Patra B, Yan J, Xie XJ, Brekken RA, Barnett CC, Bornmann WG et al (2011) Modulating endogenous NQO1 levels identifies key regulatory mechanisms of action of beta-lapachone for pancreatic cancer therapy. Clin Cancer Res 17(2):275–285

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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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