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Proceedings Paper

Mitochondrial targets of photodynamic therapy and their contribution to cell death
Author(s): Nancy L. Oleinick; Jitsuo Usuda; Liang-yan Xue; Kashif Azizuddin; Song-mao Chiu; Minh C. Lam; Rachel L. Morris; Anna-Liisa Nieminen
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Paper Abstract

In response to photodynamic therapy (PDT), many cells in culture or within experimental tumors are eliminated by apoptosis. PDT with photosensitizers that localize in or target mitochondria, such as the phthalocyanine Pc 4, causes prompt release of cytochrome c into the cytoplasm and activation of caspases-9 and -3, among other caspases, that are responsible for initiating cell degradation. Some cells appear resistant to apoptosis after PDT; however, if they have sustained sufficient damage, they will die by a necrotic process or through a different apoptotic pathway. In the case of PDT, the distinction between apoptosis and necrosis may be less important than the mechanism that triggers both processes, since critical lethal damage appears to occur during treatment and does not require the major steps in apoptosis to be expressed. We earlier showed, for example, that human breast cancer MCF-7 cells that lack caspase-3 are resistant to the induction of apoptosis by PDT, but are just as sensitive to the loss of clonogenicity as MCF-7 cells stably expressing transfected procaspase-3. Many photosensitizers that target mitochondria specifically attack the anti-apoptotic protein Bcl-2, generating a variety of crosslinked and cleaved photoproducts. Recent evidence suggests that the closely related protein Bcl-xL is also a target of Pc 4-PDT. Transient transfection of an expression vector encoding deletion mutants of Bcl-2 have identified the critical sensitive site in the protein that is required for photodamage. This region contains two alpha helices that form a secondary membrane anchorage site and are thought to be responsible for pore formation by Bcl-2. As specific protein targets are identified, we are becoming better able to model the critical events in PDT-induced cell death.

Paper Details

Date Published: 6 June 2002
PDF: 8 pages
Proc. SPIE 4612, Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XI, (6 June 2002); doi: 10.1117/12.469339
Show Author Affiliations
Nancy L. Oleinick, Case Western Reserve Univ. School of Medicine (United States)
Jitsuo Usuda, Case Western Reserve Univ. School of Medicine (United States)
Liang-yan Xue, Case Western Reserve Univ. School of Medicine (United States)
Kashif Azizuddin, Case Western Reserve Univ. School of Medicine (United States)
Song-mao Chiu, Case Western Reserve Univ. School of Medicine (United States)
Minh C. Lam, Case Western Reserve Univ. School of Medicine (United States)
Rachel L. Morris, Case Western Reserve Univ. School of Medicine (United States)
Anna-Liisa Nieminen, Case Western Reserve Univ. School of Medicine (United States)


Published in SPIE Proceedings Vol. 4612:
Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XI
Thomas J. Dougherty, Editor(s)

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