Premium
Mechanism of cell death mediated by a BF 2 ‐chelated tetraaryl‐azadipyrromethene photodynamic therapeutic: Dissection of the apoptotic pathway in vitro and in vivo
Author(s) -
O'Connor Aisling E.,
Mc Gee Margaret M.,
Likar Yury,
Ponomarev Vladimir,
Callanan John J.,
O'shea Donal F.,
Byrne Annette T.,
Gallagher William M.
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26073
Subject(s) - photodynamic therapy , in vivo , apoptosis , cancer research , unfolded protein response , in vitro , photosensitizer , programmed cell death , cancer cell , tirapazamine , mechanism of action , biology , cancer , chemistry , microbiology and biotechnology , cytotoxicity , biochemistry , genetics , organic chemistry
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 18 F‐labeled 3′‐deoxy‐3′‐fluorothymidine ( 18 F‐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.