Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Targeted photoredox catalysis in cancer cells

Nature Chemistry volume 11, pages 1041–1048 (2019)Cite this article

Subjects

Abstract

Hypoxic tumours are a major problem for cancer photodynamic therapy. Here, we show that photoredox catalysis can provide an oxygen-independent mechanism of action to combat this problem. We have designed a highly oxidative Ir(iii) photocatalyst, [Ir(ttpy)(pq)Cl]PF6 ([1]PF6, where ‘ttpy’ represents 4′-(p-tolyl)-2,2′:6′,2′′-terpyridine and ‘pq’ represents 3-phenylisoquinoline), which is phototoxic towards both normoxic and hypoxic cancer cells. Complex 1 photocatalytically oxidizes 1,4-dihydronicotinamide adenine dinucleotide (NADH)—an important coenzyme in living cells—generating NAD• radicals with a high turnover frequency in biological media. Moreover, complex 1 and NADH synergistically photoreduce cytochrome c under hypoxia. Density functional theory calculations reveal π stacking in adducts of complex 1 and NADH, facilitating photoinduced single-electron transfer. In cancer cells, complex 1 localizes in mitochondria and disrupts electron transport via NADH photocatalysis. On light irradiation, complex 1 induces NADH depletion, intracellular redox imbalance and immunogenic apoptotic cancer cell death. This photocatalytic redox imbalance strategy offers a new approach for efficient cancer phototherapy.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Structures of compounds.
Fig. 2: DFT calculations and stability of complex 1.
Fig. 3: Photoredox reaction between NADH and complex 1 under 463 nm blue-light irradiation.
Fig. 4: Cellular localization and cellular response after irradiation.
Fig. 5: Photocatalytic cycle for oxidation of NADH by complex 1, showing the production of NAD• radicals, involvement of oxygen, and reduction of cyt c.

Data availability

The data that support the findings of this study are available within the paper and its Supplementary Information files, or from the corresponding authors on reasonable request. Crystallographic data for the complex [1]PF6·(1.5 toluene) reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (under deposition number CCDC 1840366). After the Open Access agreement has been established, underpinning datasets will be deposited in Warwick’s Institutional Repository—Warwick Research Archive Portal, according to the Open Access Agreement.

References

  1. Riddell, I. A. & Lippard, S. J. Cisplatin and oxaliplatin: our current understanding of their actions. Met Ions Life Sci. 18, 1–42 (2018).

    CAS  Google Scholar 

  2. Meier-Menches, S. M., Gerner, C., Berger, W., Hartinger, C. G. & Keppler, B. K. Structure–activity relationships for ruthenium and osmium anticancer agents—towards clinical development. Chem. Soc. Rev. 47, 909–928 (2018).

    Article  CAS  PubMed  Google Scholar 

  3. Bergamo, A., Dyson, P. J. & Sava, G. The mechanism of tumour cell death by metal-based anticancer drugs is not only a matter of DNA interactions. Coord. Chem. Rev. 360, 17–33 (2018).

    Article  CAS  Google Scholar 

  4. Farrer, N. J., Salassa, L. & Sadler, P. J. Photoactivated chemotherapy (PACT): the potential of excited-state d-block metals in medicine. Dalton Trans. 10690–10701 (2009).

  5. Banerjee, S. & Chakravarty, A. R. Metal complexes of curcumin for cellular imaging, targeting, and photoinduced anticancer activity. Acc. Chem. Res. 48, 2075–2083 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Lo, K. K. W. Luminescent rhenium(i) and iridium(iii) polypyridine complexes as biological probes, imaging reagents, and photocytotoxic agents. Acc. Chem. Res. 48, 2985–2995 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Knoll, J. D. & Turro, C. Control and utilization of ruthenium and rhodium metal complex excited states for photoactivated cancer therapy. Coord. Chem. Rev. 282–283, 110–126 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu, J. et al. Harnessing ruthenium(ii) as photodynamic agents: encouraging advances in cancer therapy. Coord. Chem. Rev. 363, 17–28 (2018).

    Article  CAS  Google Scholar 

  9. Heinemann, F., Karges, J. & Gasser, G. Critical overview of the use of Ru (ii) polypyridyl complexes as photosensitizers in one-photon and two-photon photodynamic therapy. Acc. Chem. Res. 50, 2727–2736 (2017).

    Article  CAS  PubMed  Google Scholar 

  10. Shi, G. et al. Ru(ii) dyads derived from α-oligothiophenes: a new class of potent and versatile photosensitizers for PDT. Coord. Chem. Rev. 282–283, 127–138 (2015).

    Article  CAS  Google Scholar 

  11. Meggers, E. Asymmetric catalysis activated by visible light. Chem. Commun. 51, 3290–3301 (2015).

    Article  CAS  Google Scholar 

  12. Spring, B. Q., Rizvi, I., Xu, N. & Hasan, T. The role of photodynamic therapy in overcoming cancer drug resistance. Photochem. Photobiol. Sci. 14, 1476–1491 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Teicher, B. A. Hypoxia and drug resistance. Cancer Metast. Rev. 13, 139–168 (1994).

    Article  CAS  Google Scholar 

  14. Wang, H. P. et al. Phospholipid hydroperoxide glutathione peroxidase protects against singlet oxygen-induced cell damage of photodynamic therapy. Free Radical Biol. Med. 30, 825–835 (2001).

    Article  CAS  Google Scholar 

  15. Henderson, B. W. & Miller, A. C. Effects of scavengers of reactive oxygen and radical species on cell survival following photodynamic treatment in vitro: comparison to ionizing radiation. Radiat. Res. 108, 196–205 (1986).

    Article  CAS  PubMed  Google Scholar 

  16. Gomer, C. J. et al. Photodynamic therapy-mediated oxidative stress can induce expression of heat shock proteins. Cancer Res. 56, 2355–2360 (1996).

    CAS  PubMed  Google Scholar 

  17. Ruhdorfer, S., Sanovic, R., Sander, V., Krammer, B. & Verwanger, T. Gene expression profiling of the human carcinoma cell line A-431 after 5-aminolevulinic acid-based photodynamic treatment. Int. J. Oncol. 30, 1253–1262 (2007).

    CAS  PubMed  Google Scholar 

  18. Tong, Z., Singh, G. & Rainbow, A. J. Sustained activation of the extracellular signal-regulated kinase pathway protects cells from photofrin-mediated photodynamic therapy. Cancer Res. 62, 5528–5535 (2002).

    CAS  PubMed  Google Scholar 

  19. Edmonds, C., Hagan, S., Gallagher-Colombo, S. M., Busch, T. M. & Cengel, K. A. Photodynamic therapy activated signaling from epidermal growth factor receptor and STAT3: targeting survival pathways to increase PDT efficacy in ovarian and lung cancer. Cancer Biol. Ther. 13, 1463–1470 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Assefa, Z. et al. The activation of the c-Jun N-terminal kinase and p38 mitogen-activated protein kinase signaling pathways protects HeLa cells from apoptosis following photodynamic therapy with hypericin. J. Biol. Chem. 274, 8788–8796 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Kessel, D. & Erickson, C. Porphyrin photosensitization of multi-drug resistant cell types. Photochem. Photobiol. 55, 397–399 (1992).

    Article  CAS  PubMed  Google Scholar 

  22. Höckel, M. & Vaupel, P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J. Natl Cancer Inst. 93, 266–276 (2001).

    Article  PubMed  Google Scholar 

  23. Klimova, T. & Chandel, N. S. Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ. 15, 660–666 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Chiarugi, A., Dölle, C., Felici, R. & Ziegler, M. The NAD metabolome—a key determinant of cancer cell biology. Nat. Rev. Cancer 12, 741–752 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Prier, C. K. et al. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Huo, H. et al. Asymmetric photoredox transition-metal catalysis activated by visible light. Nature 515, 100–103 (2014).

    Article  CAS  PubMed  Google Scholar 

  27. Demas, J. N. et al. Oxygen sensors based on luminescence quenching. Anal. Chem. 71, 793A–800A (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Liu, Z. et al. The potent oxidant anticancer activity of organoiridium catalysts. Angew. Chem. Int. Ed. 53, 3941–3946 (2014).

    Article  CAS  Google Scholar 

  29. Ma, J. et al. Preparation of chiral-at-metal catalysts and their use in asymmetric photoredox chemistry. Nat. Protoc. 13, 605–632 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Peterson, J. R., Smith, T. A. & Thordarson, P. Synthesis and room temperature photo-induced electron transfer in biologically active bis(terpyridine) ruthenium(ii)–cytochrome c bioconjugates and the effect of solvents on the bioconjugation of cytochrome c. Org. Biomol. Chem. 8, 151–162 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Boaz, H. & Rollefson, G. K. The quenching of fluorescence. Deviations from the Stern–Volmer law. J. Am. Chem. Soc. 72, 3435–3443 (1950).

    Article  CAS  Google Scholar 

  32. Matsuzaki, S., Kotake, Y. & Humphries, K. M. Identification of mitochondrial electron transport chain-mediated NADH radical formation by EPR spin-trapping techniques. Biochemistry 50, 10792–10803 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Lapuente-Brun, E. et al. Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. Science 340, 1567–1570 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Li, H. et al. Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science 289, 1159–1164 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Margoliash, E. & Frohwirt, N. Spectrum of horse-heart cytochrome c. Biochem. J. 71, 570–572 (1959).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Huang, H. et al. Highly charged ruthenium(ii) polypyridyl complexes as lysosome-localized photosensitizers for two-photon photodynamic therapy. Angew. Chem. Int. Ed. 54, 14049–14052 (2015).

    Article  CAS  Google Scholar 

  37. Peng, Q. et al. 5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges. Cancer 79, 2282–2308 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Huang, H. et al. Real-time tracking mitochondrial dynamic remodeling with two-photon phosphorescent iridium(iii) complexes. Biomaterials 83, 321–331 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Berezin, M. Y. & Achilefu, S. Fluorescence lifetime measurements and biological imaging. Chem. Rev. 110, 2641–2684 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Berridge, M. V., Herst, P. M. & Tan, A. S. Tetrazolium dyes as tools in cell biology: new insights into their cellular reduction. Biotechnol. Annu. Rev. 11, 127–152 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Waghray, M. et al. Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts. FASEB J. 19, 854–856 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. He, Y. Y. & Häder, D. P. UV-B-induced formation of reactive oxygen species and oxidative damage of the cyanobacterium Anabaena sp.: protective effects of ascorbic acid and N-acetyl-l-cysteine. J. Photochem. Photobiol. B 66, 115–124 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Ricci, J. E. et al. Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell 117, 773–786 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Tesniere, A. et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29, 482–491 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Coverdale, J. P. C. et al. Asymmetric transfer hydrogenation by synthetic catalysts in cancer cells. Nat. Chem. 10, 347–354 (2018).

    Article  CAS  PubMed  Google Scholar 

  46. Moan, J. Effect of bleaching of porphyrin sensitizers during photodynamic therapy. Cancer Lett. 33, 45–53 (1986).

    Article  CAS  PubMed  Google Scholar 

  47. Gorrini, C., Harris, I. S. & Mak, T. W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 12, 931–947 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Porras, J. A., Mills, I. N., Transue, W. J. & Bernhard, S. Highly fluorinated Ir(iii)-2,2′:6′,2″-terpyridine–phenylpyridine–X complexes via selective C–F activation: robust photocatalysts for solar fuel generation and photoredox catalysis. J. Am. Chem. Soc. 138, 9460–9472 (2016).

    Article  CAS  PubMed  Google Scholar 

  49. Tinker, L. L. et al. Visible light induced catalytic water reduction without an electron relay. Chem. Eur. J. 13, 8726–8732 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Gȩbicki, J., Marcinek, A. & Zielonka, J. Transient species in the stepwise interconversion of NADH and NAD+. Acc. Chem. Res. 37, 379–386 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Fukuzumi, S., Inada, O. & Suenobu, T. Mechanisms of electron-transfer oxidation of NADH analogues and chemiluminescence. Detection of the keto and enol radical cations. J. Am. Chem. Soc. 125, 4808–4816 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Tanaka, M., Ohkubo, K. & Fukuzumi, S. DNA cleavage by UVA irradiation of NADH with dioxygen via radical chain processes. J. Phys. Chem. A 110, 11214–11218 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Lee, H. Y., Chen, S., Zhang, M. H. & Shen, T. Studies on the synthesis of two hydrophilic hypocrellin derivatives with enhanced absorption in the red spectral region and on their photogeneration of O2 • − and O2 (1Δg). J. Photochem. Photobiol. B 71, 43–50 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Hvasanov, D., Mason, A. F., Goldstein, D. C., Bhadbhade, M. & Thordarson, P. Optimising the synthesis, polymer membrane encapsulation and photoreduction performance of Ru(ii)-and Ir(iii)-bis(terpyridine) cytochrome c bioconjugates. Org. Biomol. Chem. 11, 4602–4612 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Sabharwal, S. S. & Schumacker, P. T. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat. Rev. Cancer 14, 709–721 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wenzel, C. et al. 3D high-content screening for the identification of compounds that target cells in dormant tumor spheroid regions. Exp. Cell Res. 323, 131–143 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Ji, J., Zhang, Y., Chen, W. R. & Wang, X. DC vaccine generated by ALA-PDT-induced immunogenic apoptotic cells for skin squamous cell carcinoma. Oncoimmunology 5, e1072674 (2016).

    Article  CAS  PubMed  Google Scholar 

  58. Galluzzi, L., Buqué, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the EPSRC (grants EP/G006792, EP/F034210/1 and EP/P030572/1 to P.J.S.; platform grant EP/P001459/1 to M.J.P.; EPSRC DTP studentship to T.M.; EP/N010825/1 to M.S.; and EP/N010825 to V.G.S.), MRC (grant G0701062 to P.J.S.), The Royal Society (Newton International Fellowship NF160307 to H.H.; and Newton-Bhahba International Fellowship NF151429 to S.B.), Leverhulme Trust (Senior Research Fellowship to V.G.S.), National Science Foundation of China (NSFC grant 21701113 to P.Z.; and 21525105, 21471164 and 21778079 to H.C.), 973 Program (2015CB856301 to H.C.), The Fundamental Research Funds for the Central Universities (to H.C.), ERC (Consolidator Grant GA 681679 PhotoMedMet to G.G.), French Government (Investissements d’Avenir grant ANR-10-IDEX-0001-02 PSL to G.G.) and the Sun Yat-sen University Startup fund (75110-18841213 to H.H.). We also thank W. Zhang, L. Song and P. Aston for assistance with mass spectrometry, J. P. C. Coverdale for assistance with ICP-MS experiments, and I. Prokes for assistance with NMR spectroscopy.

Author information

Author notes

  1. These authors contributed equally: Huaiyi Huang, Samya Banerjee.

Authors and Affiliations

  1. School of Pharmaceutical Science (Shenzhen), Sun Yat-sen University, Guangzhou, China

    Huaiyi Huang

  2. Department of Chemistry, University of Warwick, Coventry, UK

    Huaiyi Huang, Samya Banerjee, Guy J. Clarkson, Michael Staniforth, Vasilios G. Stavros & Peter J. Sadler

  3. MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-sen University, Guangzhou, China

    Kangqiang Qiu & Hui Chao

  4. College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, China

    Pingyu Zhang

  5. Department of Chemistry, University of Zurich, Zurich, Switzerland

    Olivier Blacque

  6. School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, UK

    Thomas Malcomson & Martin J. Paterson

  7. Department of Physics, University of Warwick, Coventry, UK

    Michael Staniforth & Vasilios G. Stavros

  8. Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Health and Life Sciences, Laboratory for Inorganic Chemical Biology, Paris, France

    Gilles Gasser

Authors
  1. Huaiyi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samya Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kangqiang Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pingyu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Olivier Blacque
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas Malcomson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Martin J. Paterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guy J. Clarkson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael Staniforth
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vasilios G. Stavros
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gilles Gasser
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hui Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Peter J. Sadler
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors were involved with the design and interpretation of the experiments, and with the writing of the manuscript. Chemical and biological experiments were carried out by H.H., S.B., K.Q. and P.Z. X-ray crystallography was carried out by S.B. and G.J.C. DFT calculations were carried by O.B., T.M. and M.J.P. M.S. and V.G.S. carried out the excited-state photochemistry experiments and analysed the data. H.H., S.B., H.C., G.G. and P.J.S analysed the data and co-wrote the paper. All authors discussed the results and commented on the manuscript. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Gilles Gasser, Hui Chao or Peter J. Sadler.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Tables 1–9, Figs. 1–36 and references.

Reporting Summary

Complex-1.cif

Crystallographic data for compound 1 (CCDC reference 1840366).

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, H., Banerjee, S., Qiu, K. et al. Targeted photoredox catalysis in cancer cells. Nat. Chem. 11, 1041–1048 (2019). https://doi.org/10.1038/s41557-019-0328-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-019-0328-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer