Novel zinc phthalocyanine as a promising photosensitizer for photodynamic treatment of esophageal cancer

Kuzyniak,Weronika; Schmidt,Jacob; Glac,Wojciech; Berkholz,Janine; Steinemann,Gustav; Hoffmann,Björn; Ermilov,Eugeny A.; Gürek,Ayşe Gül; Ahsen,Vefa; Nitzsche,Bianca; Höpfner,Michael

doi:10.3892/ijo.2017.3854

Novel zinc phthalocyanine as a promising photosensitizer for photodynamic treatment of esophageal cancer

Authors:
- Weronika Kuzyniak
- Jacob Schmidt
- Wojciech Glac
- Janine Berkholz
- Gustav Steinemann
- Björn Hoffmann
- Eugeny A. Ermilov
- Ayşe Gül Gürek
- Vefa Ahsen
- Bianca Nitzsche
- Michael Höpfner
View Affiliations

Affiliations: Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany, Department of Animal and Human Physiology, Faculty of Biology, University of Gdansk, Gdansk, Poland, Federal Institute for Materials Research and Testing (BAM), Division Biophotonics, Berlin, Germany, Department of Chemistry, Gebze Technical University, Gebze, Turkey
Published online on: January 17, 2017 https://doi.org/10.3892/ijo.2017.3854
Pages: 953-963

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) has gathered much attention in the field of cancer treatment and is increasingly used as an alternative solution for esophageal cancer therapy. However, there is a constant need for improving the effectiveness and tolerability of the applied photosensitizers (PS). Here, we propose tetra-triethyleneoxysulfonyl substituted zinc phthalocyanine (ZnPc) as a promising PS for photodynamic treatment of esophageal cancer. ZnPc-induced phototoxicity was studied in two human esophageal cancer cell lines: OE-33 (adenocarcinoma) and Kyse-140 (squamous cell carcinoma). In vitro studies focused on the uptake and intracellular distribution of the novel ZnPc as well as on its growth inhibitory potential, reactive oxygen species (ROS) formation and the induction of apoptosis. The chicken chorioallantoic membrane assay (CAM assay) and studies on native Wistar rats were employed to determine the antineoplastic and antiangiogenic activity of ZnPc-PDT as well as the tolerability and safety of non-photoactivated ZnPc in vivo. ZnPc was taken up by cancer cells in a dose- and time-dependent manner and showed a homogeneous cytoplasmic distribution. Photoactivation of ZnPc-loaded (1-10 µM) cells led to a dose-dependent growth inhibition of esophageal adenocarcinoma and squamous cell carcinoma cells of >90%. The antiproliferative effect was based on ROS-induced cytotoxicity and the induction of mitochondria-driven apoptosis. In vivo studies on esophageal tumor plaques grown on the CAM revealed pronounced antiangiogenic and antineoplastic effects. ZnPc-PDT caused long-lasting changes in the vascular architecture and a marked reduction of tumor feeding blood vessels. Animal studies confirmed the good tolerability and systemic safety of ZnPc, as no changes in immunological, behavioral and organic parameters could be detected upon treatment with the non-photoactivated ZnPc. Our findings show the extraordinary photoactive potential of the novel ZnPc as a photosensitizer for PDT of esophageal cancer.

View Figures

View References

1	Thrift AP: The epidemic of oesophageal carcinoma: Where are we now? Cancer Epidemiol. 41:88–95. 2016. View Article : Google Scholar : PubMed/NCBI
2	Ireland CJ, Thompson SK, Laws TA and Esterman A: Risk factors for Barrett's esophagus: A scoping review. Cancer Causes Control. 27:301–323. 2016. View Article : Google Scholar : PubMed/NCBI
3	Meves V, Behrens A and Pohl J: Diagnostics and early diagnosis of esophageal cancer. Viszeralmedizin. 31:315–318. 2015. View Article : Google Scholar
4	Chang TL, Tsai YF, Chao YK and Wu MY: Quality-of-life measures as predictors of post-esophagectomy survival of patients with esophageal cancer. Qual Life Res. 25:465–475. 2016. View Article : Google Scholar
5	Sutter AP, Höpfner M, Huether A, Maaser K and Scherübl H: Targeting the epidermal growth factor receptor by erlotinib (Tarceva) for the treatment of esophageal cancer. Int J Cancer. 118:1814–1822. 2006. View Article : Google Scholar
6	Triesscheijn M, Baas P, Schellens JHM and Stewart FA: Photodynamic therapy in oncology. Oncologist. 11:1034–1044. 2006. View Article : Google Scholar : PubMed/NCBI
7	Yi E, Yang CK, Leem C, Park Y, Chang J-E, Cho S and Jheon S: Clinical outcome of photodynamic therapy in esophageal squamous cell carcinoma. J Photochem Photobiol B. 141:20–25. 2014. View Article : Google Scholar : PubMed/NCBI
8	Shishkova N, Kuznetsova O and Berezov T: Photodynamic therapy in gastroenterology. J Gastrointest Cancer. 44:251–259. 2013. View Article : Google Scholar : PubMed/NCBI
9	Höpfner M, Maaser K, Theiss A, Lenz M, Sutter AP, Kashtan H, von Lampe B, Riecken EO, Zeitz M and Scherübl H: Hypericin activated by an incoherent light source has photodynamic effects on esophageal cancer cells. Int J Colorectal Dis. 18:239–247. 2003.PubMed/NCBI
10	Castano AP, Demidova TN and Hamblin MR: Mechanisms in photodynamic therapy: Part one-photosensitizers, photochemistry and cellular localization. Photodiagn Photodyn Ther. 1:279–293. 2004. View Article : Google Scholar
11	Liu M, Tai C, Sain M, Hu AT and Chou F: Photodynamic applications of phthalocyanines. J Photochem Photobiol Chem. 165:131–136. 2004. View Article : Google Scholar
12	Josefsen LB and Boyle RW: Photodynamic therapy: Novel third- generation photosensitizers one step closer? Br J Pharmacol. 154:1–3. 2008. View Article : Google Scholar : PubMed/NCBI
13	Jiang Z, Shao J, Yang T, Wang J and Jia L: Pharmaceutical development, composition and quantitative analysis of phthalocyanine as the photosensitizer for cancer photodynamic therapy. J Pharm Biomed Anal. 87:98–104. 2014. View Article : Google Scholar
14	Kuzyniak W, Ermilov EA, Atilla D, Gürek AG, Nitzsche B, Derkow K, Hoffmann B, Steinemann G, Ahsen V and Höpfner M: Tetra-triethyleneoxysulfonyl substituted zinc phthalocyanine for photodynamic cancer therapy. Photodiagn Photodyn Ther. 13:148–157. 2016. View Article : Google Scholar
15	Atilla D, Saydan N, Durmuş M, Gürek AG, Khan T, Rück A, Walt H, Nyokong T and Ahsen V: Synthesis and photodynamic potential of tetra- and octa-triethyleneoxysulfonyl substituted zinc phthalocyanines. J Photochem Photobiol Chem. 186:298–307. 2007. View Article : Google Scholar
16	Nitzsche B, Gloesenkamp C, Schrader M, Ocker M, Preissner R, Lein M, Zakrzewicz A, Hoffmann B and Höpfner M: Novel compounds with antiangiogenic and antiproliferative potency for growth control of testicular germ cell tumours. Br J Cancer. 103:18–28. 2010. View Article : Google Scholar : PubMed/NCBI
17	Gloesenkamp C, Nitzsche B, Lim AR, Normant E, Vosburgh E, Schrader M, Ocker M, Scherübl H and Höpfner M: Heat shock protein 90 is a promising target for effective growth inhibition of gastrointestinal neuroendocrine tumors. Int J Oncol. 40:1659–1667. 2012.PubMed/NCBI
18	Höpfner M, Huether A, Sutter AP, Baradari V, Schuppan D and Scherübl H: Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells. Biochem Pharmacol. 71:1435–1448. 2006. View Article : Google Scholar : PubMed/NCBI
19	Huether A, Höpfner M, Baradari V, Schuppan D and Scherübl H: Sorafenib alone or as combination therapy for growth control of cholangiocarcinoma. Biochem Pharmacol. 73:1308–1317. 2007. View Article : Google Scholar : PubMed/NCBI
20	Nitzsche B, Gloesenkamp C, Schrader M, Hoffmann B, Zengerling F, Balabanov S, Honecker F and Höpfner M: Anti-tumour activity of two novel compounds in cisplatin- resistant testicular germ cell cancer. Br J Cancer. 107:1853–1863. 2012. View Article : Google Scholar : PubMed/NCBI
21	Weiss A, van Beijnum JR, Bonvin D, Jichlinski P, Dyson PJ, Griffioen AW and Nowak-Sliwinska P: Low-dose angiostatic tyrosine kinase inhibitors improve photodynamic therapy for cancer: Lack of vascular normalization. J Cell Mol Med. 18:480–491. 2014. View Article : Google Scholar : PubMed/NCBI
22	Zhang Z, Jin H, Bao J, Fang F, Wei J and Wang A: Intravenous repeated-dose toxicity study of ZnPcS2P2-based-photodynamic therapy in Wistar rats. Photochem Photobiol Sci. 5:1006–1017. 2006. View Article : Google Scholar : PubMed/NCBI
23	Tiwari DK, Jin T and Behari J: Bio-distribution and toxicity assessment of intravenously injected anti-HER2 antibody conjugated CdSe/ZnS quantum dots in Wistar rats. Int J Nanomed. 6:463–475. 2011.
24	Gloesenkamp CR, Nitzsche B, Ocker M, Di Fazio P, Quint K, Hoffmann B, Scherübl H and Höpfner M: AKT inhibition by triciribine alone or as combination therapy for growth control of gastroenteropancreatic neuroendocrine tumors. Int J Oncol. 40:876–888. 2012.
25	Huang Z: A review of progress in clinical photodynamic therapy. Technol Cancer Res Treat. 4:283–293. 2005. View Article : Google Scholar : PubMed/NCBI
26	Fayter D, Corbett M, Heirs M, Fox D and Eastwood A: A systematic review of photodynamic therapy in the treatment of pre-cancerous skin conditions, Barrett's oesophagus and cancers of the biliary tract, brain, head and neck, lung, oesophagus and skin. Health Technol Assess. 14:1–288. 2010. View Article : Google Scholar : PubMed/NCBI
27	Rodrigues JR, Charris J, Ferrer R, Gamboa N, Angel J, Nitzsche B, Hoepfner M, Lein M, Jung K and Abramjuk C: Effect of quinolinyl acrylate derivatives on prostate cancer in vitro and in vivo. Invest New Drugs. 30:1426–1433. 2012. View Article : Google Scholar
28	Qumseya BJ, David W and Wolfsen HC: Photodynamic therapy for Barrett's esophagus and esophageal carcinoma. Clin Endosc. 46:30–37. 2013. View Article : Google Scholar : PubMed/NCBI
29	Mordon S, Cochrane C, Tylcz JB, Betrouni N, Mortier L and Koncar V: Light emitting fabric technologies for photodynamic therapy. Photodiagn Photodyn Ther. 12:1–8. 2015. View Article : Google Scholar
30	Oleinick NL, Morris RL and Belichenko I: The role of apoptosis in response to photodynamic therapy: What, where, why, and how. Photochem Photobiol Sci. 1:1–21. 2002. View Article : Google Scholar
31	Morgan J, Potter WR and Oseroff AR: Comparison of photodynamic targets in a carcinoma cell line and its mitochondrial DNA-deficient derivative. Photochem Photobiol. 71:747–757. 2000. View Article : Google Scholar : PubMed/NCBI
32	Shao J, Dai Y, Zhao W, Xie J, Xue J, Ye J and Jia L: Intracellular distribution and mechanisms of actions of photosensitizer Zinc(II)-phthalocyanine solubilized in Cremophor EL against human hepatocellular carcinoma HepG2 cells. Cancer Lett. 330:49–56. 2013. View Article : Google Scholar
33	Tynga IM, Houreld NN and Abrahamse H: The primary subcellular localization of Zinc phthalocyanine and its cellular impact on viability, proliferation and structure of breast cancer cells (MCF-7). J Photochem Photobiol B. 120:171–176. 2013. View Article : Google Scholar
34	Nanashima A, Isomoto H, Abo T, Nonaka T, Morisaki T, Arai J, Takagi K, Ohnita K, Shoji H, Urabe S, et al: How to access photodynamic therapy for bile duct carcinoma. Ann Transl Med. 2:232014.PubMed/NCBI
35	Huang Z, Hsu Y, Li L, Wang L, Song X-D, Yow CMN, Lei X, Musani AI, Luo R-C and Day BJ: Photodynamic therapy of cancer - Challenges of multidrug resistance. J Innov Opt Health Sci. 8:15300022015. View Article : Google Scholar
36	Juarranz A, Jaén P, Sanz-Rodríguez F, Cuevas J and González S: Photodynamic therapy of cancer. Basic principles and applications. Clin Transl Oncol. 10:148–154. 2008. View Article : Google Scholar : PubMed/NCBI
37	Gupta SC, Hevia D, Patchva S, Park B, Koh W and Aggarwal BB: Upsides and downsides of reactive oxygen species for cancer: The roles of reactive oxygen species in tumorigenesis, prevention, and therapy. Antioxid Redox Signal. 16:1295–1322. 2012. View Article : Google Scholar :
38	Nowis D, Makowski M, Stoktosa T, Legat M, Issat T and Gołab J: Direct tumor damage mechanisms of photodynamic therapy. Acta Biochim Pol. 52:339–352. 2005.PubMed/NCBI
39	Grimm S, Mvondo D, Grune T and Breusing N: The outcome of 5-ALA-mediated photodynamic treatment in melanoma cells is influenced by vitamin C and heme oxygenase-1. Biofactors. 37:17–24. 2011. View Article : Google Scholar : PubMed/NCBI
40	Nicholson DW: From bench to clinic with apoptosis-based therapeutic agents. Nature. 407:810–816. 2000. View Article : Google Scholar : PubMed/NCBI
41	Abrahamse H and Hamblin MR: New photosensitizers for photodynamic therapy. Biochem J. 473:347–364. 2016. View Article : Google Scholar : PubMed/NCBI
42	Moeno S, Krause RWM, Ermilov EA, Kuzyniak W and Höpfner M: Synthesis and characterization of novel zinc phthalocyanines as potential photosensitizers for photodynamic therapy of cancers. Photochem Photobiol Sci. 13:963–970. 2014. View Article : Google Scholar : PubMed/NCBI
43	Wang A, Li Y, Zhou L, Yuan L, Lu S, Lin Y, Zhou J and Wei S: Charge dependent photodynamic activity of alanine based zinc phthalocyanines. J Photochem Photobiol B. 141:10–19. 2014. View Article : Google Scholar : PubMed/NCBI
44	Vargas A, Zeisser-Labouèbe M, Lange N, Gurny R and Delie F: The chick embryo and its chorioallantoic membrane (CAM) for the in vivo evaluation of drug delivery systems. Adv Drug Deliv Rev. 59:1162–1176. 2007. View Article : Google Scholar : PubMed/NCBI
45	Nowak-Sliwinska P, van Beijnum JR, van Berkel M, van den Bergh H and Griffioen AW: Vascular regrowth following photodynamic therapy in the chicken embryo chorioallantoic membrane. Angiogenesis. 13:281–292. 2010. View Article : Google Scholar : PubMed/NCBI
46	Chan WM, Lim TH, Pece A, Silva R and Yoshimura N: Verteporfin PDT for non-standard indications - a review of current literature. Graefes Arch Clin Exp Ophthalmol. 248:613–626. 2010. View Article : Google Scholar : PubMed/NCBI
47	Fingar VH, Kik PK, Haydon PS, Cerrito PB, Tseng M, Abang E and Wieman TJ: Analysis of acute vascular damage after photodynamic therapy using benzoporphyrin derivative (BPD). Br J Cancer. 79:1702–1708. 1999. View Article : Google Scholar : PubMed/NCBI
48	Fukumura D and Jain RK: Tumor microvasculature and microenvironment: Targets for anti-angiogenesis and normalization. Microvasc Res. 74:72–84. 2007. View Article : Google Scholar : PubMed/NCBI