Proteasome inhibition potentiates antitumor effects of photodynamic therapy in mice through induction of endoplasmic reticulum stress and unfolded protein response.
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.
Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland.
Angelika
A
Szokalska
Marcin
M
Makowski
Dominika
D
Nowis
Grzegorz M
GM
Wilczynski
Marek
M
Kujawa
Cezary
C
Wójcik
Izabela
I
Mlynarczuk-Bialy
Pawel
P
Salwa
Jacek
J
Bil
Sylwia
S
Janowska
Patrizia
P
Agostinis
Tom
T
Verfaillie
Marek
M
Bugajski
Jan
J
Gietka
Tadeusz
T
Issat
Eliza
E
Glodkowska
Piotr
P
Mrówka
Tomasz
T
Stoklosa
Michael R
MR
Hamblin
Pawel
P
Mróz
Marek
M
Jakóbisiak
Jakub
J
Golab
D000230:Adenocarcinoma; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D017323:Dihematoporphyrin Ether / Q000627:therapeutic use*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010778:Photochemotherapy / Q000379:methods*; D011166:Porphyrins / Q000627:therapeutic use; D061988:Proteasome Inhibitors; D011489:Protein Denaturation / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D026082:Singlet Oxygen / Q000378:metabolism; D025801:Ubiquitin / Q000187:drug effects / Q000378:metabolism; D000077362:Verteporfin
D000970:Antineoplastic Agents; D011166:Porphyrins; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D025801:Ubiquitin; D000077362:Verteporfin; D026082:Singlet Oxygen; D017323:Dihematoporphyrin Ether