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Proceedings Paper

Initial targets and cellular responses to PDT
Author(s): Myriam E. Rodriguez; Kashif Azizuddin; Song-mao Chiu; Grace Delos Santos; Sheeba Joseph; Liang-yan Xue; Nancy L. Oleinick
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Paper Abstract

Pc 4, a photosensitizer first synthesized at Case Western Reserve University and now in clinical trial at University Hospitals of Cleveland, has been shown to bind preferentially and with high affinity to mitochondrial and endoplasmic reticulum membranes. Upon photoirradiation of Pc 4-loaded cells, membrane components are photodamaged. In most cancer cells, apoptosis is triggered by the initial photodamage; however, in cells deficient in one of the critical intermediates of apoptosis, this process does not occur, although the cells remain as sensitive to the lethal effects of Pc 4-PDT as the apoptosis-competent cells, when cell death is determined by colony formation. Here we report that an alternative death process, autophagy, is induced in all cells tested and becomes the dominant pathway for elimination of lethally damaged cells when apoptosis is compromised. The anti-apoptotic protein Bcl-2, when overexpressed, protects only apoptosis-competent cells against loss of clonogenicity, while the autophagy inhibitor 3-methyladenine provides a markedly greater protection to apoptosis-deficient cells. The results suggest that the primary determinant of cell death is not the final pathway for elimination of the cells but the initial photodamage to critical membrane targets. In attempts to identify those targets, we have studied the role of different membrane phospholipids in the localization of Pc 4. Cardiolipin (CL) is a phospholipid found exclusively in the mitochondrial inner membrane and at the contact sites between the inner and outer membranes. Previous fluorescence resonance energy transfer studies revealed colocalization of Pc 4 and CL, which points to CL as a possible binding site and target for Pc 4. Unilamellar liposomes with different lipid compositions were used as membrane models to test the affinity of Pc 4. As revealed by the binding constants, Pc 4 does not display preferential binding to CL in these systems. Moreover, binding affinities appear to be independent of lipid composition. Localization of Pc 4 in mitochondrial membranes is likely determined by proteins or other factors not replicated in the liposomes. Studies in cells with modified CL content could report modified binding affinities.

Paper Details

Date Published: 27 February 2007
PDF: 9 pages
Proc. SPIE 6427, Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XVI, 642703 (27 February 2007); doi: 10.1117/12.717011
Show Author Affiliations
Myriam E. Rodriguez, Case Western Reserve Univ. (United States)
Kashif Azizuddin, Case Western Reserve Univ. (United States)
Song-mao Chiu, Case Western Reserve Univ. (United States)
Grace Delos Santos, Case Western Reserve Univ. (United States)
Sheeba Joseph, Case Western Reserve Univ. (United States)
Liang-yan Xue, Case Western Reserve Univ. (United States)
Nancy L. Oleinick, Case Western Reserve Univ. (United States)

Published in SPIE Proceedings Vol. 6427:
Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XVI
David Kessel, Editor(s)

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