Mechanism of cell death mediated by a BF2-chelated tetraaryl-azadipyrromethene photodynamic therapeutic: Dissection of the apoptotic pathway in vitro and in vivo

Authors

  • Aisling E. O'Connor,

    1. UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
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  • Margaret M. Mc Gee,

    1. UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
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  • Yury Likar,

    1. Department of Radiology, Memorial Sloan Kettering Cancer Centre, New York, NY
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  • Vladimir Ponomarev,

    1. Department of Radiology, Memorial Sloan Kettering Cancer Centre, New York, NY
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  • John J. Callanan,

    1. UCD School of Agriculture, Food Science and Veterinary Medicine, Veterinary Science Centre, University College Dublin, Belfield, Dublin 4, Ireland
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  • Donal F. O'shea,

    1. Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
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  • Annette T. Byrne,

    1. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Reservoir House Sandyford Industrial Estate, Ballymoss Road, Dublin 18, Ireland
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    • A.T.B. and W.M.G contributed equally to this work.

  • William M. Gallagher

    Corresponding author
    1. UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
    • UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
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    • A.T.B. and W.M.G contributed equally to this work.


Abstract

Photodynamic therapy (PDT) is an established treatment modality for cancer. ADPM06 is an emerging non-porphyrin PDT agent which has been specifically designed for therapeutic application. Recently, we have demonstrated that ADPM06-PDT is well tolerated in vivo and elicits impressive complete response rates in various models of cancer when a short drug-light interval is applied. Herein, the mechanism of action of ADPM06-PDT in vitro and in vivo is outlined. Using a drug and light combination that reduces the clonogenicity of MDA-MB-231 cells by >90%, we detected a well-orchestrated apoptotic response accompanied by the activation of various caspases in vitro. The generation of reactive oxygen species (ROS) upon photosensitizer irradiation was found to be the key instigator in the observed apoptotic response, with the endoplasmic reticulum (ER) found to be the intracellular site of initial PDT damage, as determined by induction of a rapid ER stress response post-PDT. PDT-induced apoptosis was also found to be independent of p53 tumor suppressor status. A robust therapeutic response in vivo was demonstrated, with a substantial reduction in tumor proliferation observed, as well as a rapid induction of apoptosis and initiation of ER stress, mirroring numerous aspects of the mechanism of action of ADPM06 in vitro. Finally, using a combination of 18F-labeled 3′-deoxy-3′-fluorothymidine (18F-FLT) nuclear and optical imaging, a considerable decrease in tumor proliferation over 24-hr in two models of human cancer was observed. Taken together, this data clearly establishes ADPM06 as an exciting novel PDT agent with significant potential for further translational development.

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