David H. Kessel
David Kessel, Ph.D.
Department of Pharmacology
Wayne State University School of Medicine
540 E. Canfield
Detroit, MI 48201
Photodynamic therapy (PDT) is a process for selective treatment of pathologic conditions that are not readily treated otherwise without other adverse reactions. The process involves topical or systemic administration of photosensitizing compounds. These tend to localize in malignant tissues for reasons that are not entirely clear. Many of the photosensitizing compounds bind to circulating lipoproteins and are therefore attracted to lipoprotein receptors that are often up-regulated in malignant cells and tissues. Critical components of PDT include light and oxygen. Upon irradiation, photosensitizing agents react with photons to form an 'excited state'. The photosensitizer can release this energy in the form of fluorescence, permitting the localization of tumors. Alternatively, the energy can be passed along to oxygen dissolved in the tissues. This 'activated' form of oxygen is highly reactive, and will oxidize the first protein or lipid it encounters. This effect can result in inactivation of proteins or, in the case of lipids, form a peroxide that can become part of a chain reaction, resulting in loss of lipid functions.
Our group was the first to report that a critical target of PDT was the anti-apoptotic protein Bcl-2. This occurs when the photosensitizing agent is initially localized at sites where Bcl-2 is found--mitochondria or the endoplasmic reticulum (ER). Loss of Bcl-2 function leads to apoptosis, an irreversible form of cell death. This occurs when Bcl-2 is unable to bind (and thereby inactivate) the pro-apoptotic proteins, e.g., Bax and Bak. These proteins are then free to bind to mitochondria, resulting in release of cytochrome c and the initiation of apoptosis. Chemotherapy can also lead to apoptosis, but via an indirect route involving many signaling pathways. If any of these is defective, cells can survive chemotherapy. The more direct activation of apoptosis by PDT means that no cell can survive if sufficient drug and light are present.
A second mode of PDT-induced cell death, discovered by our group, involves lysosomes. When a photosensitizer is accumulated in lysosomes, irradiation leads to lysosomal damage, release of proteases into the cytosol, and a proteolytic attack on the protein Bid. This results in formation of a truncated Bid (t-Bid) that is capable of interacting with mitochondria, again triggering apoptosis.
Loss of Bcl-2 function can also lead to the release of yet another protein termed Beclin. Beclin then can initiate a process known as autophagy. This is generally a survival pathway, resulting in the recycling of defective organelles and of cytosolic material so that the cell can survive starvation. In the case of PDT, autophagy can promote the survival of cells that have suffered only a minor degree of photodamage. If the cells attempt to recycle too much of their contents, this can become a death pathway. We were among the first groups to appreciate the role of autophagy in the totality of the cellular responses to PDT.
Since the autophagic recycling process involves fusion of autophagic vesicles with lysosomes, photodamage to lysosomes can interrupt autophagy. This leads to the initiation of apoptosis via a pathway that is not completely understood. As a result, photodamage directed against lysosomes can be especially effective since the protective effects of autophagy are absent.
When the ER is a target for photodamage, this can result in a new mode of cell death termed paraptosis. The result is an extensive pattern of cytoplasmic vacuole formation that is not associated with apoptosis. Paraptosis can bring about the death of malignant cell types with an impaired apoptotic pathway and meu be responsible for the high degree of efficacy of PDT.
Photosensitizing agents currently being used in the clinic target either lysosomes or mitochondria and the ER. They also play another role, namely targeting of the tumor vasculature. Direct killing of tumor cells can bring about at most a 3-log kill which means that 99.9% of a tumor is destroyed. It is true that PDT has almost no adverse effects, so that re-treatment is readily feasible. If a tumor is dividing every month, a 3-log kill means that the tumor will regrow to the original size in 10 doublings, or less than a year. The eradication of the tumor vasculature brings about an additional 6-8 log kill which usually means total eradication of regions exposed to light. In the case of surface (skin) tumors, light can be applied by any source. Since red light penetrates tissues much better than green or blue, sensitizers are chosen to that they are activated by red light. Arrays of LEDs are now available that can be used for surface irradiation. If a tumor is in a lung or bladder, or in the esophagus, a laser is used, coupled to a fiber optic. One or more fibers can be placed anywhere there is access.
New research is being directed toward the development of new and better sensitizers, agents that can be activated by deep-red (penetrating) light, that are promptly cleared from the circulation and that do not photosensitize the skin or have other toxicity problems. We are currently examining the role that autophagy can play in the efficacy of PDT, along with the effect of different reactive oxygen species that are formed when the excited state of the photosensitizer reacts with oxygen. We recently reported that agents that prolong the half-life of hydrogen peroxide after PDT (via catalase inhibition) promotes PDT efficacy. We are also examining the effects of hypoxia on photodynamic effects. Tumor cells seldom see the 20% oxygen level commonly used for cell culture. Studies with a hypoxia chamber are expected to reveal more pertinent information on the determinants of successful tumor eradication by PDT.
Our work on PDT has now been supported by the NIH since 1978. Dr. Kessel organizes an annual meeting in San Francisco every January, devoted to presentations of PDT research involving clinical, pre-clinical and engineering advances. He organized an International PDT conference in Seattle in June, 2009.
Kessel D, Oleinick N. Perspective: Cell death pathways associated with photodynamic therapy: an update. Photochem Photobiol 2018;94:213-18.
Kessel D, Reiners, J. Effects of combined lysosomal and mitochondrial photodamage in a non small-Cell lung cancer cell line: the role of paraptosis. Photochem. Photobiol. 2017:93:1502-8.
Kessel D, Sub-cellular targeting as a determinant of the efficacy of photodynamic therapy. Photochem Photobiol. 2017;93:609-12.
Kessel D, Evans C. Promotion of pro-Apoptotic signals by lysosomal photodamage: mechanistic aspects and influence of autophagy. Photochem Photobiol 2016;92:620-3.
Kessel D, Photodynamic therapy: promotion of efficacy by a sequential protocol. J Porph Phthalo 2016;20:302-6.
Kessel, D, Autophagic death probed by photodynamic therapy. Autophagy 2015;11:1941-3
Education and Training:
PhD (1959) University of Michigan, Ann Arbor, Michigan