This project is designed to continue an exploration of early responses to photodynamic therapy (PDT), a procedure that involves irradiation of photosensitized cells and tissues. PDT circumvents many common drug- resistance mechanisms encountered in cancer chemotherapy and can lead to effective cancer control. PDT was initially (ca. 1975) thought to kill cells via membrane photodamage. We now know that the process is much more complex, with both apoptosis and autophagy plahying important roles. In this proposal we have identified three aims. We propose to: [1] explore the role of autophagy as a factor in cell death vs. survival in PDT;[2] characterize the effects of PDT on the endocytic pathway;[3] assess the contributions and roles of different reactive oxygen species on initiation of apoptosis and autophagy. Studies in the 1990s established apoptosis as a common mechanism of photokilling but not until 2006 was it realized that autophagy was also a component of survival vs. death decisions. Our knowledge of PDT responses continues to evolve and now includes such determinants of efficacy as canonical vs. non-canonical routes to autophagy and the evocation of apoptosis via indirect routes. While apoptosis is an irreversible route to death, autophagy can serves as a survival pathway, introducing a 'shoulder'on the dose-response curve, or as a death pathway. The result appears to depends on the PDT target, intrinsic cellular capacity for apoptosis and autophagy and other characteristics of the cell phenotype. An additional factor may be the pathway to autophagy elicited by PDT: canonical vs non-canonical. The latter is said to lead to cell death, but this may represent a special case. Protection from photokilling can occur even when autophagy is incomplete, i.e., without the fusion of auto- phagosomes with lysosomes followed by proteolysis of the encapsulated cargo. The nature of reactive oxygen species (ROS) induced by PDT also plays a role in promotion of apoptosis and autophagy. Enhanced H O 2 2 production was found to lead to the promotion of apoptosis, an effect we attribute to the long persistence of this species in the cellular environment. Moreover, both H O and !O S have been suggested as potential 2 2 2 initiating factors for autophagy. An exploration of the role of different ROS as determinants of PDT efficacy is therefore proposed. We have recently found that PDT evokes a hitherto unreported cellular response: impaired membrane trafficking leading to interference with the endocytic pathway. The implications of this effect remain to be explored.

Public Health Relevance

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 PDT-induced cell death pathways and their role in cancer control is also expected to assist in drug development and to provide a better under- standing of the role of death pathways in cancer control. Optimal targets for PDT remain to be identified

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA023378-31
Application #
8249330
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Wong, Rosemary S
Project Start
1983-08-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
31
Fiscal Year
2012
Total Cost
$255,105
Indirect Cost
$87,273
Name
Wayne State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Kessel, David; Reiners Jr, John J (2014) Enhanced efficacy of photodynamic therapy via a sequential targeting protocol. Photochem Photobiol 90:889-95
Kessel, David (2014) Reversible effects of photodamage directed toward mitochondria. Photochem Photobiol 90:1211-3
Price, Michael; Heilbrun, Lance; Kessel, David (2013) Effects of the oxygenation level on formation of different reactive oxygen species during photodynamic therapy. Photochem Photobiol 89:683-6
Kessel, David; Price, Michael (2012) Evaluation of diethyl-3-3'-(9,10-anthracenediyl)bis acrylate as a probe for singlet oxygen formation during photodynamic therapy. Photochem Photobiol 88:717-20
Andrzejak, Michelle; Santiago, Marie; Kessel, David (2011) Effects of endosomal photodamage on membrane recycling and endocytosis. Photochem Photobiol 87:699-706
Andrzejak, Michelle; Price, Michael; Kessel, David H (2011) Apoptotic and autophagic responses to photodynamic therapy in 1c1c7 murine hepatoma cells. Autophagy 7:979-84
Agostinis, Patrizia; Berg, Kristian; Cengel, Keith A et al. (2011) Photodynamic therapy of cancer: an update. CA Cancer J Clin 61:250-81
Reiners Jr, John J; Kleinman, Miriam; Kessel, David et al. (2011) Nonesterified cholesterol content of lysosomes modulates susceptibility to oxidant-induced permeabilization. Free Radic Biol Med 50:281-94
Kessel, David (2011) Inhibition of endocytic processes by photodynamic therapy. Lasers Surg Med 43:542-7
Kessel, David; Price, Michael; Caruso, Joseph et al. (2011) Effects of photodynamic therapy on the endocytic pathway. Photochem Photobiol Sci 10:491-8

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