6 March 2006 Nuclear transcription factors: a new approach to enhancing cellular responses to ALA-mediated photodynamic therapy
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Abstract
Photodynamic therapy (PDT) using aminolevulinic acid (ALA) relies upon the uptake of ALA into cancer cells, where it is converted into a porphyrin intermediate, protoporphyrin IX (PpIX) that is highly photosensitizing. For large or resistant tumors, however, ALA/PDT is often not completely effective due to inadequate PpIX levels. Therefore, new approaches to enhance the intracellular production of PpIX are sought. Here, we describe a general approach to improve intracellular PpIX accumulation via manipulations that increase the expression of an enzyme, coproporphyrinogen oxidase (CPO), that is rate-determining for PpIX production. We show that nuclear hormones that promote terminal differentiation, e.g. vitamin D or androgens, can also increase the accumulation of PpIX and the amount of killing of the target cells upon exposure to light. These hormones bind to intracellular hormone receptors that translocate to the nucleus, where they act as transcription factors to increase the expression of target genes. We have found that several other transcription factors associated with terminal differentiation, including members of the CCAAT enhancer binding (C/EBP) family, and a homeobox protein named Hoxb13, are also capable of enhancing PpIX accumulation. These latter transcription factors appear to interact directly with the CPO gene promoter, resulting in enhanced CPO transcriptional activity. Our data in several different cell systems, including epithelial cells of the skin and prostate cancer cells, indicate that enhancement of CPO expression and PpIX accumulation represents a viable new approach toward improving the efficacy of ALA/PDT.
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Edward V. Maytin, Edward V. Maytin, Sanjay Anand, Sanjay Anand, Nobuyuki Sato, Nobuyuki Sato, Brian Moore, Brian Moore, Judith Mack, Judith Mack, Christopher Gasbarre, Christopher Gasbarre, Samantha Keevey, Samantha Keevey, Bernhard Ortel, Bernhard Ortel, Alok Sinha, Alok Sinha, Amor Khachemoune, Amor Khachemoune, "Nuclear transcription factors: a new approach to enhancing cellular responses to ALA-mediated photodynamic therapy", Proc. SPIE 6139, Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XV, 613909 (6 March 2006); doi: 10.1117/12.646880; https://doi.org/10.1117/12.646880
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