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Aminopyrimidoisoquinolinequinone (APIQ) redox cycling is potentiated by ascorbate and induces oxidative stress leading to necrotic-like cancer cell death

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Summary

Several phenylaminopyrimidoisoquinolinequinones (APIQs) were tested for their cytotoxicity against different cancer cell lines (K562, T24, HepG2) in the presence or absence of ascorbate. Ascorbate enhanced the toxic effects of quinones with first half-wave potential EI 1/2 values in the range of −480 to −660 mV. Phenylaminoquinones that were unsubstituted at position 6 exhibited greater cytotoxic activity than did their 6-methyl-substituted analogues. Two groups of compounds were further selected, namely 8–10 and 20–22, to study the cellular mechanisms involved in quinone cytotoxicity. Indeed, these compounds have the same range of redox potentials but differed considerably in their capacity to induce cell death. In the presence of ascorbate, the cell demise induced by compounds 8–10 was not caspase-3 dependent, as shown by the lack of activation of caspase-3 and the absence of cleaved PARP fragments. In addition, an index of ER stress (eIF2α phosphorylation) was activated by these compounds. Quinones 8–10 decreased the cellular capacity to reduce MTT dye and caused marked ATP depletion. Taken together, our results show that ascorbate enhances quinone redox-cycling and leads to ROS formation that inhibits cell proliferation and provokes caspase-independent cell death. Interestingly, we also observed that quinone 8 had a rather selective effect given that freshly isolated peripheral blood leukocytes from human healthy donors were more resistant than human leukemia K562 cells.

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References

  1. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70. doi:10.1016/s0092-8674(00)81683-9

    Article  PubMed  CAS  Google Scholar 

  2. Korynevska A, Heffeter P, Matselyukh B, Elbling L, Micksche M, Stoika R, Berger W (2007) Mechanisms underlying the anticancer activities of the angucycline landomycin E. Biochem Pharmacol 74(12):1713–1726. doi:10.1016/j.bcp.2007.08.026

    Article  PubMed  CAS  Google Scholar 

  3. Kuntsmann MP, Mitscher LA (1966) The structural characterization of tetrangomycin and tetrangulol. J Org Chem 31(9):2920–2925. doi:10.1021/jo01347a043

    Article  PubMed  CAS  Google Scholar 

  4. Oka M, Kamei H, Hamagishi Y, Tomita K, Miyaki T, Konishi M, Oki T (1990) Chemical and biological properties of rubiginone, a complex of new antibiotics with vincristine-cytotoxicity potentiating activity. J Antibiot 43(8):967–976

    Article  PubMed  CAS  Google Scholar 

  5. Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8(7):579–591. doi:10.1038/nrd2803

    Article  PubMed  CAS  Google Scholar 

  6. Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z, Pelicano H, Chiao PJ, Achanta G, Arlinghaus RB, Liu J, Huang P (2006) Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell 10(3):241–252. doi:10.1016/j.ccr.2006.08.009

    Article  PubMed  CAS  Google Scholar 

  7. Verrax J, Stockis J, Tison A, Taper HS, Calderon PB (2006) Oxidative stress by ascorbate/menadione association kills K562 human chronic myelogenous leukaemia cells and inhibits its tumour growth in nude mice. Biochem Pharmacol 72(6):671–680. doi:10.1016/j.bcp.2006.05.025

    Article  PubMed  CAS  Google Scholar 

  8. Verrax J, Delvaux M, Beghein N, Taper H, Gallez B, Buc Calderon P (2005) Enhancement of quinone redox cycling by ascorbate induces a caspase-3 independent cell death in human leukaemia cells. An in vitro comparative study. Free Radical Res 39(6):649–657. doi:10.1080/10715760500097906

    Article  CAS  Google Scholar 

  9. Verrax J, Cadrobbi J, Marques C, Taper H, Habraken Y, Piette J, Calderon P (2004) Ascorbate potentiates the cytotoxicity of menadione leading to an oxidative stress that kills cancer cells by a non-apoptotic caspase-3 independent form of cell death. Apoptosis 9(2):223–233. doi:10.1023/B:APPT.0000018804.26026.1a

    Article  PubMed  CAS  Google Scholar 

  10. Benites J, Rojo L, Valderrama JA, Taper H, Calderon PB (2008) Part 1: effect of vitamin C on the biological activity of two euryfurylbenzoquinones on TLT, a murine hepatoma cell line. Eur J Med Chem 43(9):1813–1817. doi:10.1016/j.ejmech.2007.11.015

    Article  PubMed  CAS  Google Scholar 

  11. Benites J, Valderrama JA, Taper H, Buc Calderon P (2010) An in vitro comparative study with furyl-1,4-quinones endowed with anticancer activities. Invest New Drugs:1–8. doi:10.1007/s10637-010-9419-1

  12. Benites J, Valderrama JA, Bettega K, Pedrosa RC, Calderon PB, Verrax J (2010) Biological evaluation of donor-acceptor aminonaphthoquinones as antitumor agents. Eur J Med Chem 45(12):6052–6057. doi:10.1016/j.ejmech.2010.10.006

    Article  PubMed  CAS  Google Scholar 

  13. Benites J, Valderrama JA, Taper H, Buc Calderon P (2009) Part 2: influence of 2-euryfuryl-1,4-naphthoquinone and its peri-hydroxy derivatives on both cell death and metabolism of TLT cells, a murine hepatoma cell line. modulation of cytotoxicity by vitamin C. Chem Pharm Bull 57(6):615–619. doi:10.1248/cpb.57.615

    Article  PubMed  CAS  Google Scholar 

  14. Vásquez D, Rodríguez JA, Theoduloz C, Calderon PB, Valderrama JA (2010) Studies on quinones. Part 46. Synthesis and in vitro antitumor evaluation of aminopyrimidoisoquinolinequinones. Eur J Med Chem 45(11):5234–5242. doi:10.1016/j.ejmech.2010.08.040

    Article  PubMed  Google Scholar 

  15. Vásquez D, Rodríguez JA, Theoduloz C, Verrax J, Calderon PB, Valderrama JA (2009) Synthesis and antitumor evaluation of 8-phenylaminopyrimido[4,5-c]isoquinolinequinones. Bioorg Med Chem Lett 19(17):5060–5062. doi:10.1016/j.bmcl.2009.07.041

    Article  PubMed  Google Scholar 

  16. Wroblewski F, Ladue JS (1955) Lactic dehydrogenase activity in blood. Proc Soc Exp Biol Med 90(1):210–213

    PubMed  CAS  Google Scholar 

  17. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63. doi:10.1016/0022-1759(83)90303-4

    Article  PubMed  CAS  Google Scholar 

  18. Lowry O, Rosebrough N, Farr L, Randall R (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 183:265–275

    Google Scholar 

  19. Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA et al (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376(6535):37–43. doi:10.1038/376037a0

    Article  PubMed  CAS  Google Scholar 

  20. Valderrama JA, Andrea Ibacache J, Arancibia V, Rodriguez J, Theoduloz C (2009) Studies on quinones. Part 45: novel 7-aminoisoquinoline-5,8-quinone derivatives with antitumor properties on cancer cell lines. Biorg Med Chem 17(7):2894–2901. doi:10.1016/j.bmc.2009.02.013

    Article  CAS  Google Scholar 

  21. Fernandes-Alnemri T, Litwack G, Alnemri ES (1994) CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme. J Biol Chem 269(49):30761–30764

    PubMed  CAS  Google Scholar 

  22. Debiton E, Madelmont JC, Legault J, Barthomeuf C (2003) Sanguinarine-induced apoptosis is associated with an early and severe cellular glutathione depletion. Cancer Chemother Pharmacol 51(6):474–482. doi:10.1007/s00280-003-0609-9

    PubMed  CAS  Google Scholar 

  23. Kaufman RJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13(10):1211–1233

    Article  PubMed  CAS  Google Scholar 

  24. Sheikh MS, Fornace AJ Jr (1999) Regulation of translation initiation following stress. Oncogene 18(45):6121–6128. doi:10.1038/sj.onc.1203131

    Article  PubMed  CAS  Google Scholar 

  25. Dejeans N, Tajeddine N, Beck R, Verrax J, Taper H, Gailly P, Calderon PB (2010) Endoplasmic reticulum calcium release potentiates the ER stress and cell death caused by an oxidative stress in MCF-7 cells. Biochem Pharmacol 79(9):1221–1230. doi:10.1016/j.bcp.2009.12.009

    Article  PubMed  CAS  Google Scholar 

  26. Powis G (1987) Metabolism and reactions of quinoid anticancer agents. Pharmacol Ther 35(1–2):57–162. doi:10.1016/0163-7258(87)90105-7

    Article  PubMed  CAS  Google Scholar 

  27. Roginsky VA, Barsukova TK, Stegmann HB (1999) Kinetics of redox interaction between substituted quinones and ascorbate under aerobic conditions. Chem Biol Interact 121(2):177–197. doi:10.1016/s0009-2797(99)00099-x

    Article  PubMed  CAS  Google Scholar 

  28. Jarabak R, Jarabak J (1995) Effect of ascorbate on DT-diaphorase-mediated redox cycling of 2-methyl-1,4-naphthoquinone. Arch Biochem Biophys 318(2):418–423

    Article  PubMed  CAS  Google Scholar 

  29. Kroemer G, El-Deiry WS, Golstein P, Peter ME, Vaux D, Vandenabeele P, Zhivotovsky B, Blagosklonny MV, Malorni W, Knight RA, Piacentini M, Nagata S, Melino G (2005) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ 12(Suppl 2):1463–1467. doi:10.1038/sj.cdd.4401724

    Article  PubMed  CAS  Google Scholar 

  30. Ghose AK, Crippen GM (1987) Atomic physicochemical parameters for three-dimensional-structure-directed quantitative structure-activity relationships. 2. Modeling dispersive and hydrophobic interactions. J Chem Inf Comput Sci 27(1):21–35. doi:10.1021/ci00053a005

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors expressed their gratitude to FONDECYT (Grant n° 1060591) and CONICYT-WBI (Belgium) for financial support.

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Authors and Affiliations

  1. Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago, Chile

    David R. Vásquez & Jaime A. Valderrama

  2. Toxicology and Cancer Biology Research Group, GTOX 7369, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain, Bruxelles, Belgium

    Julien Verrax & Pedro Buc Calderon

  3. Departamento de Ciencias Quımicas y Farmacéuticas, Universidad Arturo Prat, Casilla 121, Iquique, Chile

    Pedro Buc Calderon

  4. Instituto de EtnoFarmacología (IDE), Universidad Arturo Prat, Casilla 121, Iquique, Chile

    David R. Vásquez, Jaime A. Valderrama & Pedro Buc Calderon

Authors
  1. David R. Vásquez
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  2. Julien Verrax
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  3. Jaime A. Valderrama
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  4. Pedro Buc Calderon
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Correspondence to Pedro Buc Calderon.

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Figure S1

(a) Relation between half-wave potential (EI 1/2) and potentiation index of compounds 1, 3–10 of group A; and 2, 13–22 of group B. (b) Relation between lipophilicity (Log P) and potentiation index of compounds 1, 3–10 of group A; and 2, 13–22 of group B. (DOC 188 kb)

Figure S2

T-24 cells were incubated for 4 h without any compound (control), with sanguinarine (10 μM), with quinone 8 (10 μM) alone, or with quinone 8 plus ascorbate (2 mM). They were then double stained with annexin-V and propidium iodide and observed by fluorescence microscopy, as described in the Materials and Methods section. (DOC 6629 kb)

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Vásquez, D.R., Verrax, J., Valderrama, J.A. et al. Aminopyrimidoisoquinolinequinone (APIQ) redox cycling is potentiated by ascorbate and induces oxidative stress leading to necrotic-like cancer cell death. Invest New Drugs 30, 1003–1011 (2012). https://doi.org/10.1007/s10637-011-9661-1

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