13 July 2009 Improvement of anti-tumor activity of photodynamic therapy through inhibition of cytoprotective mechanism in tumor cells
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Proceedings Volume 7380, Photodynamic Therapy: Back to the Future; 73804F (2009) https://doi.org/10.1117/12.822929
Event: 12th World Congress of the International Photodynamic Association, 2009, Seattle, Washington, United States
Abstract
Photodynamic therapy (PDT) leads to oxidative damage of cellular macromolecules, including numerous proteins that undergo multiple modifications such as fragmentation, cross-linking and carbonylation that result in protein unfolding and aggregation. Several mechanisms are involved in the protective responses to PDT that include activation of transcription factors, heat shock proteins, antioxidant enzymes and antiapoptotic pathways. Identification of these cytoprotective mechanisms might result in the design of more effective combination strategies to improve the antitumor efficacy of PDT. By using various molecular biology approaches, including microarray-based technologies we have identified genes that are up-regulated following PDT. Subsequent experiments revealed that some of these gene products can become targets for the combined therapeutic regimens encompassing PDT and selective small-molecule inhibitors. These include superoxide dismutase (SOD-2), cyclooxygenase 2 (COX-2), heme oxygenase 1 (HO-1), and proteins engaged in signaling endoplasmatic reticulum (ER) stress and unfolded protein response (UPR). Since a major mechanism for elimination of carbonylated proteins is their degradation by proteasomes, we hypothesized that a combination of PDT with proteasome inhibitors might lead to accumulation of carbonylated proteins in ER, aggravated ER stress and potentiated cytotoxicity towards tumor cells. Indeed, we observed that incubation of tumor cells with three different proteasome inhibitors, including bortezomib, MG132 and PSI gave increased accumulation of carbonylated and ubiquitinated proteins in PDT-treated cells. Proteasome inhibitors effectively sensitized tumor cells to PDT-mediated cytotoxicity and augmented antitumor effects of PDT in vivo.
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Dominika Nowis, Dominika Nowis, Angelika Szokalska, Angelika Szokalska, Marcin Makowski, Marcin Makowski, Magdalena Winiarska, Magdalena Winiarska, Jakub Golab, Jakub Golab, } "Improvement of anti-tumor activity of photodynamic therapy through inhibition of cytoprotective mechanism in tumor cells", Proc. SPIE 7380, Photodynamic Therapy: Back to the Future, 73804F (13 July 2009); doi: 10.1117/12.822929; https://doi.org/10.1117/12.822929
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