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Photodynamic therapy (PDT) is a process for selective treatment of cancer and certain other pathologic conditions. The process involves topical or systemic administration of photosensitizing compounds that 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 receptors that are often up-regulated in malignant cells and tissues.
A critical component is the need for light. 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 results in formation of ‘reactive oxygen species’ that can oxidize proteins or lipids. The result is protein inactivation or, in the case of lipids, formation of peroxides that can become part of a chain reaction, resulting in loss of lipid functions. The important point is that damage is confined to cells that have accumulated photosensitizers, resulting in a high degree of selectivity.
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, also identified by our group, involves lysosomes. When a photosensitizer is accumulated in lysosomes, irradiation leads to release of lysosomal proteases into the cytoplasm and a proteolytic attack on the protein Bid. This results in formation of ‘truncated Bid’ (t-Bid) that is capable of interacting with mitochondria, again triggering apoptosis. We have recently been exploring paraptosis as a death mode that can be initiated by ER photodamage and is operable in cells with impaired routes to apoptosis.
Photosensitizing agents currently being used in the clinic target either lysosomes or mitochondria and the ER. They also play another role: the 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. Since PDT has almost no adverse effects, 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. This can result in total tumor eradication.
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 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.
Research by other groups is directed toward the development of new and better sensitizers; agents that can be activated by deep-red (penetrating) light, that clear out promptly from the circulation and do not photosensitize the skin or have other toxicity problems.
Recent research has revealed that a low level of lysosomal photodamage can result in the promotion of the pro-apoptotic effect of both PDT and chemotherapy. An example is shown in the bar graph.
The photosensitizer BPD directs photodamage to mitochondria, inducing a pro-apoptotic signal. The dose selected provided a 50% level of photokilling. NPe6 causes photosensitization of lysosomes. The low PDT dose used here killed only approx.10% of the cell population. When this preceded BPD PDT, the level of photokilling was greater than 90%.
The study described above was carried out in a 2D culture of murine hepatoma cells. The effect can be also be reproduced in tumor cells of human origin in a 3D system, where the cells grow not on a glass slide, but in a three-dimensional configuration that can be less responsive to PDT because if intrinsic protective mechanisms. It appears that the pro-apoptotic signal generated by a low level of lysosomal photodamage can enhance the efficacy of any agent capable of inducing apoptosis, including chemotherapeutic agents. The mechanism and implications of these findings are currently being examined.
More recently, we have been examining the role of a new death mode termed 'paraptosis' that can occur after photodamage directed at the ER. This death mode is independent of apoptosis and can be operative on cell types with an impaired apoptotic response. Paraptosis may be implicated in examples of PDT-induced eradication of tumors that are'resistant' to therapy designed to evoke an apoptotic response.
Our work on PDT has now been supported by the NIH since 1980, Dr. Kessel organizes an annual conference in San Francisco every February, devoted to presentations of PDT research involving clinical, pre-clinical and engineering advances. He organized an International PDT conference in Seattle in June, 2009, and participates in meetings of the American & European Societies for Photobiology and the International Conference on Porphyrins and Phthalocyanines and has received Lifetime Achievement awards from both groups.
H-R C Kim PhD
Department of Pathology
John Reiners Jr., Ph.D.,
Environmental Health Sciences, WSU
Graça Vicente, Ph.D. and Kevin M Smith, Ph.D.
Department of Chemistry, Louisiana State University
Conor L Evans, Ph.D.,
Wellman Laboratories.MGH/Harvard Medical School
Imran Rizvi PhD, University of North Carolina
Girgis Obaid, PhD. University of Texas at Dallas
BS Chemistry MIT 1952
MS Chemistry University of Michigan 1954
PhD Biochemistry University of Michigan 1959
Postdoctoral training, Harvard Medical School 1960-64
Areas of Expertise
Areas of Interest
Areas of Research
Awards and Honors
Wayne State University Distinguished Faculty Award 1989-1990
WSU Academy of Scholars 1990; President 2009-2010
Dean’s Research Excellence Award, 1998, 2014
Distinguished Graduate Faculty Award, 2000
Lifetime Achievement Award ICPP 2008
Lifetime Achievement Award, American Society for Photobiology 2012
Lawrence M Weiner Award, WSU School of Medicine 2012
Lifetime Achievement Award International Photodynamic Association 2017
NIH CA 23378
Last 3 years:
Obaid, G., Jin, W., Bano, S., Kessel, D. and T. Hasan. Nanolipid formulations of benzoporphyrin derivative: exploring the dependence of nanoconstruct photophysics and photochemistry on their therapeutic index in ovarian cancer cells. Photochem Photobiol 95, 364-377, 2019.
Kessel D. Apoptosis, paraptosis and autophagy: death and survival pathways associated with photodynamic therapy. Photochem Photobiol 95, 119-125, 2019.
Rizvi I, Nath S, Obaid G, Ruhi MK, Moore K, Bano S, Kessel D, Hasan T. A combination of visudyne and a lipid-anchored liposomal formulation of benzoporphyrin derivative enhances photodynamic therapy efficacy in a 3D model for ovarian cancer. Photochem Photobiol 95, 419-429, 2019.
Spring BQ, Kessel D. 3D Culture models of malignant mesothelioma reveal a powerful interplay between photodynamic therapy and kinase suppression offering hope to reduce tumor recurrence. Photochem. Photobiol 95, 462-463, 2019.
Kessel D. Pathways to paraptosis after ER photodamage in OVCAR-5 cells. Photochem Photobiol 95, 1239-1242, 2019.
Kessel D. Photodynamic therapy: a brief history. J Clin Med 8, 1581; doi:10,3990/jcm8101581, 2019.
Kessel D, Cho WJ, Rakowski J, Kim HE, Kim HC. Effects of HPV status on responsiveness to ionizing radiation vs. photodynamic therapy in head and neck cancer cell lines. Photochem Photobiol. 96, 652-657, 2020.
Kessel D, Thomas J Dougherty, an appreciation. Photochem Photobiol 96, 454-457, 2020.
Kessel D, Photodynamic therapy: apoptosis, paraptosis and beyond. Apoptosis 25, 611-615, 2020.
Kessel D, Paraptosis and photodynamic therapy: a progress report. Photochem Photobiol. 96, 1096-1100, 2020.
Kessel D, Hypericin accumulation as a determinant of PDT efficacy. Photochem Photobiol. 96, 1144-1147, 2020.
Kessel D, Exploring modes of photokilling by hypericin. Photochem Photobiol. 96, 1101-1104, 2020.
Kessel D, Detection of paraptosis after photodynamic therapy. Springer Protocols. In Press 2021.
Kessel D, Photodynamic therapy: autophagy and mitophagy, apoptosis and paraptosis. Autophagy 16, 2098-2101, 2020.
Kessel D, Cho WJ, RakowskiJ, Kim HE Kim, H-R C. Research report: characteristics of an impaired PDT response. Photochem. Photobiol In Press 2021.
Cho WJ, Kessel D, Rakowski J, Loughery B, Najy AJ, Pham T, Kim S., Kwon YT, Kato I, Kim HE, Kim H-R C. Photodynamic therapy as a potent radiosensitizer in head and neck squamous cell carcinoma Cancers. In Press 2021.