Skip to main content
SpringerLink
Log in

A molecular insight into the phototoxic reactions observed with vemurafenib, a first-line drug against metastatic melanoma

  • Paper
  • Published:
Photochemical & Photobiological Sciences Aims and scope Submit manuscript

Abstract

The electronic properties of vemurafenib (VB) provide a rational basis for understanding its strong UVA-induced phototoxicity. Thus, solvation of hydrophobic VB by hydrogen bonding solvents controls its photophysical, photochemical and photosensitizing properties. Addition of phosphate buffered saline (PBS) to methanol (MeOH) induces a bathochromic shift of the VB absorbance spectrum and a fluorescence emission (λmax = 450 nm, quantum yield (Φ) = 0.011). Phosphorescence (λmax = 461 nm) is observed at 77 K in MeOH. 308 nm laser flash spectroscopy demonstrates that the lifetimes (τ) and quantum yields of the VB triplet state in deaerated MeOH (τMeOH = 0.41 μs, λmax ∼ 380 nm), MeOH–PBS and HSA solutions markedly depend on the microenvironment. A long-lived radical (half-life >200 μs) is also formed. The state is quenched by O2 and electron donors (Cys and 2′-deoxyguanosine) at a rate constant >1 × 109 M−1 s−1. UVA-irradiation of VB in air-saturated MeOH or MeOH–PBS solutions produces a UVA-absorbing photoproduct (Φ ∼ 5 × 10−4). VB photosensitizes Trp destruction by type I (radical formation) and type II (singlet oxygen (1O2) formation) photodynamic reactions (Φ = 0.005). Singlet oxygen production is further demonstrated by the VB-photosensitized His oxidation (ΦMeOH = 0.006).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. J. T. Lee, L. Li, P. A. Brafford, M. van den Eijnden, M. B. Halloran, K. Sproesser, N. K. Haass, K. S. Smalley, J. Tsai, G. Bollag, M. Herlyn, Pigm. Cell Melanoma Res., 2010, 23, 820–827.

    Article  CAS  Google Scholar 

  2. P. B. Chapman, A. Hauschild, C. Robert, J. B. Haanen, P. Ascierto, J. Larkin, R. Dummer, C. Garbe, A. Testori, M. Maio, D. Hogg, P. Lorigan, C. Lebbe, T. Jouary, D. Schadendorf, A. Ribas, S. J. O’Day, J. A. Sosman, J. M. Kirkwood, A. M. Eggermont, B. Dreno, K. Nolop, J. Li, B. Nelson, J. Hou, R. J. Lee, K. T. Flaherty, G. A. McArthur, N. Engl. J. Med., 2011, 364, 2507–2516.

    Article  CAS  Google Scholar 

  3. G. A. McArthur, P. B. Chapman, C. Robert, J. Larkin, J. B. Haanen, R. Dummer, A. Ribas, D. Hogg, O. Hamid, P. A. Ascierto, C. Garbe, A. Testori, M. Maio, P. Lorigan, C. Lebbe, T. Jouary, D. Schadendorf, S. J. O’Day, J. M. Kirkwood, A. M. Eggermont, B. Dreno, J. A. Sosman, K. T. Flaherty, M. Yin, I. Caro, S. Cheng, K. Trunzer, A. Hauschild, Lancet Oncol., 2014, 15, 323–332.

    Article  CAS  Google Scholar 

  4. R. Dummer, J. Rinderknecht, S. M. Goldinger, N. Engl. J. Med., 2012, 366, 480–481.

    Article  CAS  Google Scholar 

  5. P. Gelot, H. Dutartre, A. Khammari, A. Boisrobert, C. Schmitt, J. C. Deybach, J. M. Nguyen, S. Seite, B. Dreno, Exp. Dermatol., 2013, 22, 297–298.

    Article  CAS  Google Scholar 

  6. OECD, OECD Guidelines for the Testing of Chemicals, Section, 2004, vol, 4.

  7. FDA/Center for Drug Evaluation and Research, Division of Drug Oncology products (HFD-150), 2011.

  8. C. Brugière, A. Stefan, C. Morice, E. Cornet, A. Moreau, S. Allouche, L. Verneuil, Br. J. Dermatol., 2014, 171, 1529–1532.

    Article  Google Scholar 

  9. E. Kohen, R. Santus and J. G. Hirschberg, Photobiology, Academic Press, San Diego, 1995.

    Google Scholar 

  10. A. Sharma, S. R. Shah, H. Illum, J. Dowell, Drugs, 2012, 72, 2207–2222.

    Article  CAS  Google Scholar 

  11. C. A. Parker, Photoluminescence of Solutions, Elsevier, Amsterdam, 1968.

    Google Scholar 

  12. I. Tirache, P. Morlière, Redox Rep., 1995, 1, 105–111.

    Article  CAS  Google Scholar 

  13. W. A. Waterval, J. L. Scheijen, M. M. Ortmans-Ploemen, C. D. Habets-van der Poel, J. Bierau, Clin. Chim. Acta, 2009, 407, 36–42.

    Article  CAS  Google Scholar 

  14. J. K. Kamal, L. Zhao, A. H. Zewail, Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 13411–13416.

    Article  CAS  Google Scholar 

  15. S. M. Boudon, U. Plappert-Helbig, A. Odermatt, D. Bauer, Toxicol. Sci., 2014, 137, 259–267.

    Article  CAS  Google Scholar 

  16. E. G. Hohenstein, C. D. Sherrill, J. Phys. Chem. A, 2009, 113, 878–886.

    Article  CAS  Google Scholar 

  17. Protein Data Bank.

  18. V. Lhiaubet-Vallet, F. Bosca, M. A. Miranda, J. Phys. Chem. B, 2007, 111, 423–431.

    Article  CAS  Google Scholar 

  19. R. Battino, T. R. Rettich, T. Tominaga, J. Phys. Chem. Ref. Data, 1983, 12, 163–168.

    Article  CAS  Google Scholar 

  20. A. Guha, D. Panda, Int. J. Chem. Sci., 2008, 6, 1147–1167.

    CAS  Google Scholar 

  21. S. Steenken, S. V. Jovanovic, J. Am. Chem. Soc., 1997, 119, 617–618.

    Article  CAS  Google Scholar 

  22. P. Morlière, F. Bosca, M. A. Miranda, J. V. Castell, R. Santus, Photochem. Photobiol., 2004, 80, 535–541.

    Article  Google Scholar 

  23. A. A. Gorman, L. Hamblett, M. A. J. Rodgers, J. Am. Chem. Soc., 1984, 106, 4679–4682.

    Article  CAS  Google Scholar 

  24. C. Chahidi, M. Aubailly, A. Momzikoff, M. Bazin, R. Santus, Photobiochem. Photobiophys., 1981, 33, 641–649.

    Article  CAS  Google Scholar 

  25. G. Winter, H. Shioyama, U. Steiner, Chem. Phys. Lett., 1981, 81, 547–552.

    Article  CAS  Google Scholar 

  26. M. Bazin, L. K. Patterson, R. Santus, J. Phys. Chem., 1983, 87, 189–190.

    Article  CAS  Google Scholar 

  27. K. Gollnick, in Radiation Research: Biochemical, Chemical and Physical Perspectives, ed. O. F. Nygaard, H. I. Adler and W. D. Sinclair, Academic Press, New York, 1975, pp. 590–611.

  28. F. Wilkinson, J. G. Brummer, J. Phys. Chem. Ref. Data, 1981, 10, 809–999.

    Article  CAS  Google Scholar 

  29. A. Salvador, D. Vedaldi, P. Brun, S. Dall’Acqua, Toxicol. in Vitro, 2014, 28, 803–811.

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM, U1088, 1 rue des Louvels, Amiens, 80037, France

    P. Morlière & J. C. Mazière

  2. CHU Amiens-Picardie, Pôle Biologie, D408, Amiens, 80054, France

    P. Morlière, A. Galmiche, J. C. Mazière & V. Nourry

  3. Université de Picardie Jules Verne, UFR de Pharmacie, 1 rue des Louvels, Amiens, 80036, France

    P. Morlière

  4. Instituto de Tecnología Química UPV-CSIC, Universidade Politécnica de Valencia, Avenida de Los Naranjos s/n, Valencia, 46022, Spain

    F. Boscá

  5. Department of Chemistry and QOPNA, University of Aveiro, Aveiro, 3810-193, Portugal

    A. M. S. Silva

  6. Hospital de Santa Maria, Faculdade de Medicina de Lisboa, 1699 Lisboa Codex, Portugal

    A. Teixeira, J. Ferreira & P. Filipe

  7. Université de Picardie Jules Verne, UFR de Pharmacie, EA4666 1 rue des Louvels, Amiens, 80036, France

    A. Galmiche

  8. Université de Picardie Jules Verne, UFR de Médecine, 1 rue des Louvels, Amiens, 80036, France

    J. C. Mazière

  9. Muséum National d’Histoire Naturelle, Département RDDM, 43 rue Cuvier, Paris, 75231, France

    R. Santus

Authors
  1. P. Morlière
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Boscá
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. M. S. Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Teixeira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Galmiche
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. C. Mazière
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V. Nourry
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R. Santus
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. P. Filipe
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Morlière, P., Boscá, F., Silva, A.M.S. et al. A molecular insight into the phototoxic reactions observed with vemurafenib, a first-line drug against metastatic melanoma. Photochem Photobiol Sci 14, 2119–2127 (2015). https://doi.org/10.1039/c5pp00231a

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1039/c5pp00231a

Search

Navigation