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Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Angelika Szokalska¹, Marcin Makowski¹, Dominika Nowis¹, Grzegorz M. Wilczyski^2,3, Marek Kujawa², Cezary Wójcik⁴, Izabela Mynarczuk-Biay², Pawel Salwa¹, Jacek Bil¹, Sylwia Janowska¹, Patrizia Agostinis⁵, Tom Verfaillie⁵, Marek Bugajski¹, Jan Gietka¹, Tadeusz Issat¹, Eliza Godkowska¹, Piotr Mrówka¹, Tomasz Stoklosa¹, Michael R. Hamblin⁶, Pawe Mróz⁶, Marek Jakóbisiak¹ and Jakub Golab¹

Departments of ¹ Immunology and ² Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw; ³ Laboratory of Molecular and Systemic Neuromorphology, M. Nencki Institute of Experimental Biology, Warsaw, Poland; ⁴ Department of Anatomy and Cell Biology, Indiana University School of Medicine-Evansville, Evansville, Indiana; ⁵ Department of Molecular and Cell Biology, Catholic University of Leuven, Campus Gasthuisberg, Leuven, Belgium; and ⁶ Department of Dermatology, Harvard Medical School and Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts

Requests for reprints: Jakub Golab, Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, 1A Banacha Street, F Building, 02-097 Warsaw, Poland. Phone: 48-22-5992199; Fax: 48-22-5992194; E-mail: jakub.golab{at}wum.edu.pl.

Key Words: photodynamic therapy • Photofrin • proteasome • bortezomib • cancer

Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity toward tumor cells by inducing production of reactive oxygen species such as singlet oxygen. PDT leads to oxidative damage of cellular macromolecules, including proteins that undergo multiple modifications such as fragmentation, cross-linking, and carbonylation that result in protein unfolding and aggregation. Because the 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 endoplasmic reticulum (ER), aggravated ER stress, and potentiated cytotoxicity toward tumor cells. We observed that Photofrin-mediated PDT leads to robust carbonylation of cellular proteins and induction of unfolded protein response. Pretreatment 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 of murine (EMT6 and C-26) as well as human (HeLa) origin to PDT-mediated cytotoxicity. Significant retardation of tumor growth with 60% to 100% complete responses was observed in vivo in two different murine tumor models (EMT6 and C-26) when PDT was combined with either bortezomib or PSI. Altogether, these observations indicate that combination of PDT with proteasome inhibitors leads to potentiated antitumor effects. The results of these studies are of immediate clinical application because bortezomib is a clinically approved drug that undergoes extensive clinical evaluations for the treatment of solid tumors. [Cancer Res 2009;69(10):4235–43]