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David Kessel, Ph.D. |
RESEARCH INTERESTS:
Photodynamic therapy (PDT) is a process for selective treatment of pathologic conditions that are not readily treated otherwise without other adverse reactions that may be of considerable significance. The process involves topical or systemic administration of photosensitizing compounds that will be described later. 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.
A critical component of PDT 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 ‘activated’ form of oxygen is highly reactive, and will oxidize the first protein or lipid it encounters. This effect can result in inactivation of the biologic role of the protein or, in the case of lipids, form a peroxide that can become part of a chain reaction, resulting in loss of lipid functions.
PDT Targets
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, although 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.
Clinical PDT
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. 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.
PDT Research
New research is being directed toward the development of new and better sensitizers, which generally means agents that can be activated by deep-red (penetrating) light, that clear out promptly from the circulation, that do not photosensitize the skin or have other toxicity problems. Many workers are using combinations of PDT + agents designed to promote better targeting, or inhibit any process a cell might develop to circumvent photodamage. We are currently examining the role 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 Bcl-2 antagonists can substantially promote the lethality of PDT in cell culture.
Our work on PDT has now been supported by the NIH since 1978, Dr. Kessel organizes an annual meeting in San Jose every January, devoted to presentations of PDT research involving clinical, pre-clinical and engineering advances. He will organize an International PDT conference in Seattle in June, 2009.
Current Lab personnel
Ann Marie Santiago (research assistant)
Nakaiya Okan-Mensah (research assistant)
Michael Price (graduate student in Cancer Biology)
Collaborators
Graça Vicente and Kevin M Smith
Department of Chemistry, Louisiana State University
John Reiners Jr
Environmental Health Sciences, WSU
Albert Girotti
Medical College of Wisconsin
Kathryn Woodburn
Affymax, Sunnyvale CA
Jerome Horwitz
Professor Emeritus, Wayne State University
Recent references
Kessel D, Death pathways associated with photodynamic therapy. Med Laser Appl. 21, 219-224, 2006.
Kessel D, Reiners Jr, JJ. Initiation of apoptosis and autophagy by the Bcl-2 antagonist HA14-1 Cancer Lett 249, 294-299, 2007.
Kessel D, Reiners JJ. Apoptosis and autophagy after mitochondrial or endoplasmic reticulum photodamage. Photochem Photobiol 83, 1024-1028, 2007.
Kessel D and Segarra Arroyo A. , Apoptotic and autophagic responses to Bcl-2 inhibition and photodamage, Photochem. Photobiol. Sci., 6, 1290-1295, 2007.
Kessel D. Promotion of PDT efficacy by a Bcl-2 antagonist. Photochem Photobiol 84, 809-814, 2008.
Kessel D, Price M, Reiners JJ Jr. On the Role of ROS in the Pro-Apoptotic Effects of the Bcl-2 Antagonist HA14-1. Photochem Photobiol 84, 809-814, 2008.
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