Low dose of GRP78-targeting subtilase cytotoxin improves the efficacy of photodynamic therapy in vivo

Gabrysiak,Magdalena; Wachowska,Malgorzata; Barankiewicz,Joanna; Pilch,Zofia; Ratajska,Anna; Skrzypek,Ewa; Winiarska,Magdalena; Domagala,Antoni; Rygiel,Tomasz  P.; Jozkowicz,Alicja; Boon,Louis; Golab,Jakub; Firczuk,Malgorzata

doi:10.3892/or.2016.4723

Low dose of GRP78-targeting subtilase cytotoxin improves the efficacy of photodynamic therapy in vivo

Authors:
- Magdalena Gabrysiak
- Malgorzata Wachowska
- Joanna Barankiewicz
- Zofia Pilch
- Anna Ratajska
- Ewa Skrzypek
- Magdalena Winiarska
- Antoni Domagala
- Tomasz P. Rygiel
- Alicja Jozkowicz
- Louis Boon
- Jakub Golab
- Malgorzata Firczuk
View Affiliations

Affiliations: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland, Department of Pathology, Center of Biostructure Research, Medical University of Warsaw, 02-004 Warsaw, Poland, Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kracow, Poland, EPIRUS Biopharmaceuticals Netherlands BV, 3584 CM Utrecht, The Netherlands
Published online on: April 1, 2016 https://doi.org/10.3892/or.2016.4723
Pages: 3151-3158
Copyright: © Gabrysiak et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Photodynamic therapy (PDT) exerts direct cytotoxic effects on tumor cells, destroys tumor blood and lymphatic vessels and induces local inflammation. Although PDT triggers the release of immunogenic antigens from tumor cells, the degree of immune stimulation is regimen-dependent. The highest immunogenicity is achieved at sub-lethal doses, which at the same time trigger cytoprotective responses, that include increased expression of glucose-regulated protein 78 (GRP78). To mitigate the cytoprotective effects of GRP78 and preserve the immunoregulatory activity of PDT, we investigated the in vivo efficacy of PDT in combination with EGF-SubA cytotoxin that was shown to potentiate in vitro PDT cytotoxicity by inactivating GRP78. Treatment of immunocompetent BALB/c mice with EGF-SubA improved the efficacy of PDT but only when mice were treated with a dose of EGF-SubA that exerted less pronounced effects on the number of T and B lymphocytes as well as dendritic cells in mouse spleens. The observed antitumor effects were critically dependent on CD8+ T cells and were completely abrogated in immunodeficient SCID mice. All these results suggest that GRP78 targeting improves in vivo PDT efficacy provided intact T-cell immune system.

View Figures

View References

1	Agostinis P, Berg K, Cengel KA, Foster TH, Girotti AW, Gollnick SO, Hahn SM, Hamblin MR, Juzeniene A, Kessel D, et al: Photodynamic therapy of cancer: An update. CA Cancer J Clin. 61:250–281. 2011. View Article : Google Scholar : PubMed/NCBI
2	Firczuk M, Nowis D and Gołąb J: PDT-induced inflammatory and host responses. Photochem Photobiol Sci. 10:653–663. 2011. View Article : Google Scholar : PubMed/NCBI
3	Korbelik M, Krosl G, Krosl J and Dougherty GJ: The role of host lymphoid populations in the response of mouse EMT6 tumor to photodynamic therapy. Cancer Res. 56:5647–5652. 1996.PubMed/NCBI
4	Korbelik M and Cecic I: Contribution of myeloid and lymphoid host cells to the curative outcome of mouse sarcoma treatment by photodynamic therapy. Cancer Lett. 137:91–98. 1999. View Article : Google Scholar : PubMed/NCBI
5	Garg AD, Krysko DV, Verfaillie T, Kaczmarek A, Ferreira GB, Marysael T, Rubio N, Firczuk M, Mathieu C, Roebroek AJ, et al: A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J. 31:1062–1079. 2012. View Article : Google Scholar : PubMed/NCBI
6	Korbelik M, Sun J and Cecic I: Photodynamic therapy-induced cell surface expression and release of heat shock proteins: Relevance for tumor response. Cancer Res. 65:1018–1026. 2005.PubMed/NCBI
7	Henderson BW, Gollnick SO, Snyder JW, Busch TM, Kousis PC, Cheney RT and Morgan J: Choice of oxygen-conserving treatment regimen determines the inflammatory response and outcome of photodynamic therapy of tumors. Cancer Res. 64:2120–2126. 2004. View Article : Google Scholar : PubMed/NCBI
8	Kabingu E, Oseroff AR, Wilding GE and Gollnick SO: Enhanced systemic immune reactivity to a Basal cell carcinoma associated antigen following photodynamic therapy. Clin Cancer Res. 15:4460–4466. 2009. View Article : Google Scholar : PubMed/NCBI
9	Korbelik M and Cecic I: Enhancement of tumour response to photodynamic therapy by adjuvant mycobacterium cell-wall treatment. J Photochem Photobiol B. 44:151–158. 1998. View Article : Google Scholar : PubMed/NCBI
10	Wachowska M, Gabrysiak M, Muchowicz A, Bednarek W, Barankiewicz J, Rygiel T, Boon L, Mroz P, Hamblin MR and Golab J: 5-Aza-2′-deoxycytidine potentiates antitumour immune response induced by photodynamic therapy. Eur J Cancer. 50:1370–1381. 2014. View Article : Google Scholar : PubMed/NCBI
11	Jalili A, Makowski M, Switaj T, Nowis D, Wilczynski GM, Wilczek E, Chorazy-Massalska M, Radzikowska A, Maslinski W, Biały L, et al: Effective photoimmunotherapy of murine colon carcinoma induced by the combination of photodynamic therapy and dendritic cells. Clin Cancer Res. 10:4498–4508. 2004. View Article : Google Scholar : PubMed/NCBI
12	Xue LY, Agarwal ML and Varnes ME: Elevation of GRP-78 and loss of HSP-70 following photodynamic treatment of V79 cells: Sensitization by nigericin. Photochem Photobiol. 62:135–143. 1995. View Article : Google Scholar : PubMed/NCBI
13	Luo B and Lee AS: The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene. 32:805–818. 2013. View Article : Google Scholar
14	Paton AW, Beddoe T, Thorpe CM, Whisstock JC, Wilce MC, Rossjohn J, Talbot UM and Paton JC: AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP. Nature. 443:548–552. 2006. View Article : Google Scholar : PubMed/NCBI
15	Paton AW, Srimanote P, Talbot UM, Wang H and Paton JC: A new family of potent AB(5) cytotoxins produced by Shiga toxigenic Escherichia coli. J Exp Med. 200:35–46. 2004. View Article : Google Scholar : PubMed/NCBI
16	Wang H, Paton JC and Paton AW: Pathologic changes in mice induced by subtilase cytotoxin, a potent new Escherichia coli AB5 toxin that targets the endoplasmic reticulum. J Infect Dis. 196:1093–1101. 2007. View Article : Google Scholar : PubMed/NCBI
17	Harama D, Koyama K, Mukai M, Shimokawa N, Miyata M, Nakamura Y, Ohnuma Y, Ogawa H, Matsuoka S, Paton AW, et al: A subcytotoxic dose of subtilase cytotoxin prevents lipopolysaccharide-induced inflammatory responses, depending on its capacity to induce the unfolded protein response. J Immunol. 183:1368–1374. 2009. View Article : Google Scholar : PubMed/NCBI
18	Backer JM, Krivoshein AV, Hamby CV, Pizzonia J, Gilbert KS, Ray YS, Brand H, Paton AW, Paton JC and Backer MV: Chaperone-targeting cytotoxin and endoplasmic reticulum stress-inducing drug synergize to kill cancer cells. Neoplasia. 11:1165–1173. 2009. View Article : Google Scholar : PubMed/NCBI
19	Firczuk M, Gabrysiak M, Barankiewicz J, Domagala A, Nowis D, Kujawa M, Jankowska-Steifer E, Wachowska M, Glodkowska-Mrowka E, Korsak B, et al: GRP78-targeting subtilase cytotoxin sensitizes cancer cells to photodynamic therapy. Cell Death Dis. 4:e7412013. View Article : Google Scholar : PubMed/NCBI
20	Greulich H, Chen TH, Feng W, Jänne PA, Alvarez JV, Zappaterra M, Bulmer SE, Frank DA, Hahn WC, Sellers WR, et al: Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med. 2:e3132005. View Article : Google Scholar : PubMed/NCBI
21	Makowski M, Grzela T, Niderla J, ŁAzarczyk M, Mróz P, Kopeé M, Legat M, Strusińska K, Koziak K, Nowis D, et al: Inhibition of cyclooxygenase-2 indirectly potentiates antitumor effects of photodynamic therapy in mice. Clin Cancer Res. 9:5417–5422. 2003.PubMed/NCBI
22	Szokalska A, Makowski M, Nowis D, Wilczynski GM, Kujawa M, Wójcik C, Mlynarczuk-Bialy I, Salwa P, Bil J, Janowska S, et al: Proteasome inhibition potentiates antitumor effects of photodynamic therapy in mice through induction of endoplasmic reticulum stress and unfolded protein response. Cancer Res. 69:4235–4243. 2009. View Article : Google Scholar : PubMed/NCBI
23	Korbelik M: Induction of tumor immunity by photodynamic therapy. J Clin Laser Med Surg. 14:329–334. 1996.PubMed/NCBI
24	Kabingu E, Vaughan L, Owczarczak B, Ramsey KD and Gollnick SO: CD8⁺ T cell-mediated control of distant tumours following local photodynamic therapy is independent of CD4⁺ T cells and dependent on natural killer cells. Br J Cancer. 96:1839–1848. 2007. View Article : Google Scholar : PubMed/NCBI
25	Castano AP, Mroz P, Wu MX and Hamblin MR: Photodynamic therapy plus low-dose cyclophosphamide generates antitumor immunity in a mouse model. Proc Natl Acad Sci USA. 105:5495–5500. 2008. View Article : Google Scholar : PubMed/NCBI