Mechanism of cell death mediated by a BF(2)-chelated tetraaryl-azadipyrromethene photodynamic therapeutic: Dissection of the apoptotic pathway in vitro and in vivo Journal Article


Authors: O'Connor, A. E.; Mc Gee, M. M.; Likar, Y.; Ponomarev, V.; Callanan, J. J.; O'Shea, D. F.; Byrne, A. T.; Gallagher, W. M.
Article Title: Mechanism of cell death mediated by a BF(2)-chelated tetraaryl-azadipyrromethene photodynamic therapeutic: Dissection of the apoptotic pathway in vitro and in vivo
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. Copyright © 2011 UICC.
Keywords: controlled study; unclassified drug; human cell; cancer growth; nonhuman; antineoplastic agent; mouse; animal tissue; cell death; apoptosis; animal experiment; in vivo study; enzyme activation; in vitro study; caspase; protein p53; drug mechanism; reactive oxygen metabolite; 3' fluorothymidine f 18; photodynamic therapy; optical imaging; endoplasmic reticulum stress; 18f-flt nuclear imaging; bf2-chelated tetraaryl-azadipyrromethene; adpm 06
Journal Title: International Journal of Cancer
Volume: 130
Issue: 3
ISSN: 0020-7136
Publisher: John Wiley & Sons  
Date Published: 2012-02-01
Start Page: 705
End Page: 715
Language: English
DOI: 10.1002/ijc.26073
PROVIDER: scopus
PUBMED: 21413012
PMCID: PMC5568043
DOI/URL:
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 3 January 2012" - "CODEN: IJCNA" - "Source: Scopus"
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MSK Authors
  1. Vladimir Ponomarev
    102 Ponomarev
  2. Yury N Likar
    7 Likar