This project is designed to explore pathways and determinants of cell death induced by photodynamic therapy (PDT), a form of cancer treatment that circumvents most drug-resistance mechanisms. An understanding of death pathways is expected to increase our knowledge of factors in PDT efficacy (cells killed per photon absorbed). PDT can induce an apoptotic response if the cell phenotype permits. If apoptosis is impaired, another death pathway will be utilized; this doubtless contributes to PDT successes. In an exploration of alternative pathways, we found substantial evidence that autophagy accompanies photodamage as cells attempt to survive, but can also be a death pathway if apoptosis is impaired. Autophagy can promote survival by the internal digestion and recycling of cellular components, and by eliminating damaged organelles. In the contect of PDT, we propose that autophagy can either enhance survival or be a pathway to cell death. The latter appears to predominate when the cell phenotype prevents apoptosis. We plan to examine death pathways as a function of cell type (carcinoma, leukemia/ lymphoma, non-malignant) and the PDT target. The Bcl-2 antagonist HA14-1 will be utilized to assess consequences of Bcl-2 inactivation since this protein is often a PDT target and its loss can trigger both apoptosis and auto- phagy. Results will be correlated with PDT dose, photodamage sites and clonogenic viability studies. Since many proteins involved in the autophagic program are membrane-bound, a search for photodamage to such proteins is considered important. Methods for assessing apoptosis are well-defined, and involve detection of caspase activation, DNA fragmentation to endonucleosomes and chromatin condensation. Autophagy is currently characterized by formation of double-membrane intracellular vesicles containing cellular organelles and cytosol, and processing of the Atg8 ortholog LC3. Experiments are planned to assess the degree of protection from photokilling offered by autophagy and the ultimate nature of the cell death that initially involves extensive cell vacuolization and LC3 processing. Effects of PDT targets and a sub-contract with LSU will provide a synthetic capacity for preparation of photosensitizers and inhibitors that are not commercially available. Significance: The ability of PDT to mediate direct photokilling of tumor cells, e.g., at surgical margins, can be an important aid in tumor eradication. Information on mechanisms of cell death pathways and their role in cancer control is also expected to assist in drug development and to provide better understanding of the role of death pathways in cancer control. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Radiation Therapeutics and Biology Study Section (RTB)
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Wong, Rosemary S
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Wayne State University
Schools of Medicine
United States
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Kessel, David (2018) Apoptosis, Paraptosis and Autophagy: Death and Survival Pathways Associated with Photodynamic Therapy. Photochem Photobiol :
Kessel, David; Reiners Jr, John J (2017) Effects of Combined Lysosomal and Mitochondrial Photodamage in a Non-small-Cell Lung Cancer Cell Line: The Role of Paraptosis. Photochem Photobiol 93:1502-1508
Kessel, David (2017) Subcellular Targeting as a Determinant of the Efficacy of Photodynamic Therapy. Photochem Photobiol 93:609-612
Kessel, David (2016) Photodynamic therapy: Promotion of efficacy by a sequential protocol. J Porphyr Phthalocyanines 20:302-306
Kessel, David; Evans, Conor L (2016) Promotion of Proapoptotic Signals by Lysosomal Photodamage: Mechanistic Aspects and Influence of Autophagy. Photochem Photobiol 92:620-3
Kessel, David (2015) Apoptosis and associated phenomena as a determinants of the efficacy of photodynamic therapy. Photochem Photobiol Sci 14:1397-402
Aggarwal, Neha; Santiago, Ann Marie; Kessel, David et al. (2015) Photodynamic therapy as an effective therapeutic approach in MAME models of inflammatory breast cancer. Breast Cancer Res Treat 154:251-62
Kessel, David (2015) Autophagic death probed by photodynamic therapy. Autophagy 11:1941-3
Gibbs, Jaime H; Zhou, Zehua; Kessel, David et al. (2015) Synthesis, spectroscopic, and in vitro investigations of 2,6-diiodo-BODIPYs with PDT and bioimaging applications. J Photochem Photobiol B 145:35-47
Kessel, David; Reiners Jr, John J (2015) Promotion of Proapoptotic Signals by Lysosomal Photodamage. Photochem Photobiol 91:931-6

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