11 February 2008 Lysosome vs. mitochondrion as photosensitizer binding site: how does the tortoise overtake the hare?
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Abstract
Pc 4, a photosensitizer first synthesized at Case Western Reserve University and now in clinical trial at University Hospitals Case Medical Center, 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, especially the anti-apoptotic protein Bcl-2, are photodamaged. Apoptosis, as indicated by activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase, is triggered by the initial photodamage. A series of analogues of Pc 4 has been synthesized containing two axial ligands, one identical to the single ligand of Pc 4 and the other either the same as the Pc 4 ligand or bearing one or more hydroxyl groups. The hydroxyl-bearing axial ligands reduce the aggregation of the Pc in polar environments and direct the Pc's to lysosomes. Photoirradiation of cells that have taken up these Pc's into their lysosomes is 4-6 times more efficient at killing cells, as defined by loss of clonogenicity, than with Pc 4. Whereas PDT with Pc 4 photodamages Bcl-2 and Bcl-xL over the same dose response range as for cell killing, PDT with Pc 181 or the other lysosome-localizing Pc's causes much less photodamage to Bcl-2 relative to cell killing. Furthermore, in the case of the lysosome-bound Pc's, little or no caspase-3-dependent apoptosis is observed.
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Nancy L. Oleinick, Nancy L. Oleinick, Kashif Azizuddin, Kashif Azizuddin, Song-mao Chiu, Song-mao Chiu, Sheeba Joseph, Sheeba Joseph, Myriam E. Rodriguez, Myriam E. Rodriguez, Liang-yan Xue, Liang-yan Xue, Ping Zhang, Ping Zhang, Malcolm E. Kenney, Malcolm E. Kenney, Minh Lam, Minh Lam, Anna-Liisa Nieminen, Anna-Liisa Nieminen, } "Lysosome vs. mitochondrion as photosensitizer binding site: how does the tortoise overtake the hare?", Proc. SPIE 6845, Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XVII, 684505 (11 February 2008); doi: 10.1117/12.769226; https://doi.org/10.1117/12.769226
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