Photodynamic therapy (PDT) is gradually becoming an alternative method in the treatment of several diseases. Here, we investigated the role of oxygen in photodynamically treated cervical cancer cells (HeLa). The effect of PDT on HeLa cells was assessed by exposing cultured cells to disulphonated zinc phthalocyanine (ZnPcS2) and tetrasulphonated zinc tetraphenylporphyrin (ZnTPPS4). Fluorescence microscopy revealed their different localizations within the cells. ZnTPPS4 seems to be mostly limited to the cytosol and lysosomes, whereas ZnPcS2 is most likely predominantly attached to membrane structures, including plasmalemma and the mitochondrial membrane. Phototoxicity assays of PDT-treated cells carried out under different partial pressures of oxygen showed dose-dependent responses. Interestingly, ZnPcS2 was also photodynamically effective at a minimal level of oxygen, under a nitrogen atmosphere. On the other hand, hyperbaric oxygenation did not lead to a higher PDT efficiency of either photosensitizer. Although both photosensitizers can induce a significant drop in mitochondrial membrane potential, ZnPcS2 has a markedly higher effect on mitochondrial respiration that was completely blocked after two short light cycles. In conclusion, our observations suggest that PDT can be effective even in hypoxic conditions if a suitable sensitizer is chosen, such as ZnPcS2, which can inhibit mitochondrial respiration.
This is a preview of subscription content,to check access.
Access this article
Kwiatkowski S, Knap B, Przystupski D, Saczko J, Kędzierska E, Knap-Czop K, Kotlińska J, Michel O, Kotowski K, Kulbacka J (2018) Photodynamic therapy - mechanisms, photosensitizers and combinations. Biomed Pharmacother 106:1098–1107
van den Bergh H (1986) Light and porphyrins in cancer therapy. Chem Br 22:430–439
Castano AP, Demidova TN, Hamblin MR (2005) Mechanisms in photodynamic therapy: part two - cellular signaling, cell metabolism and modes of cell death. Photodiagn Photodyn Ther 2:1–23
Robertson CA, Evans DH, Abrahamse H (2009) Photodynamic therapy (PDT): a short review on cellular mechanisms and cancer research applications for PDT. J Photochem Photobiol B Biol 96:1–8
Luksiene Z (2003) Photodynamic therapy: mechanism of action and ways to improve the efficiency of treatment. Med (Kaunas) 39:1137–1150
Juzeniene A, Moan J (2007) The history of PDT in Norway. Photodiagn Photodyn Ther 4:3–11
Nowak-Stepniowska A, Pergoł P, Padzik-Graczyk A (2013) Photodynamic method of cancer diagnosis and therapy - mechanisms and applications. Postepy Biochem 59:53–63
Fischer SM, Jain KK, Braun E, Lehr S (1988) Handbook of hyperbaric oxygen therapy. Springer, Berlin
Neves A, Abrantes A, Pires A, Teixo R, Botelho MF (2016) Hyperbaric oxygen therapy combined with photodynamic therapy as a new therapeutic approach against retinoblastoma. Eur J Cancer 61:144
Bajgar R, Kolarova H, Bolek L, Binder S, Pizova K, Hanakova A (2014) High oxygen partial pressure increases photodynamic effect on HeLa cell lines in the presence of chloraluminium phthalocyanine. Anticancer Res 34:4095–4099
Jirsa M Jr, Pouckova P, Dolezal J, Pospisil J, Jirsa M (1991) Hyperbaric oxygen and photodynamic therapy in tumor bearing nude mice. Eur J Cancer 27:109
Fuchs J, Thiele J (1998) The role of oxygen in cutaneous photodynamic therapy. Free Radic Biol Med 24:835–847
Moan J, Berg K (1991) The photodegradation of porphyrins in cells can be used to estimate the lifetime of singlet oxygen. Photochem Photobiol 53:549–553
Castano AP, Demidova TN, Hamblin MR (2004) Mechanisms in photo-dynamic therapy: part one: photosensitizers, photochemistry and cellular localization. Photodiagn Photodyn Ther 1:279–293
Krestyn E, Kolarova H, Bajgar R, Tomankova K (2010) Photodynamic properties of ZnTPPS4, ClAlPcS2 and ALA in human melanoma G361 cells. Toxicol in Vitro 24:286–291
Wilson BC, Patterson MS (2008) The physics, biophysics and technology of photodynamic therapy. Phys Med Biol 53:61–109
Kriska T, Korytowski W, Girotti AW (2002) Hyperresistance to photosensitized lipid peroxidation and apoptotic killing in 5-aminolevulinate-treated tumor cells overexpressing mitochondrial GPX4. Free Radic Biol Med 33:1389–1402
Kessel D (2002) Relocalization of cationic porphyrins during photodynamic therapy. Photochem Photobiol Sci 1:837–840
Furre IE, Shahzidi S, Luksiene Z, Moller MT, Borgen E, Morgan J, Tkacz-Stachowska K, Nesland JM, Peng Q (2005) Targeting PBR by hexaminolevulinate-mediated photodynamic therapy induces apoptosis through translocation of apoptosis-inducing factor in human leukemia cells. Cancer Res 65:11051–11060
Ichinose S, Usuda J, Hirata T, Inoue T, Ohtani K, Maehara S, Kubota M, Imai K, Tsunoda Y, Kuroiwa Y, Yamada K, Tsutsui H, Furukawa K, Okunaka T, Oleinick NL, Kato H (2006) Lysosomal cathepsin initiates apoptosis, which is regulated by photodamage to Bcl-2 at mitochondria in photodynamic therapy using a novel photosensitizer, ATX-s10 (Na). Int J Oncol 29:349–355
Ji Z, Yang G, Vasovic V, Cunderlikova B, Suo Z, Nesland JM, Peng Q (2006) Subcellular localization pattern of protoporphyrin IX is an important determinant for its photodynamic efficiency of human carcinoma and normal cell lines. J Photochem Photobiol B Biol 84:213–220
Kessel D, Castelli M (2001) Evidence that bcl-2 is the target of three photosensitizers that induce a rapid apoptotic response. Photochem Photobiol 74:318–322
Lam M, Oleinick NL, Nieminen AL (2001) Photodynamic therapy-induced apoptosis in epidermoid carcinoma cells. Reactive oxygen species and mitochondrial inner membrane permeabilization. J Biol Chem 276:47379–47386
Usuda J, Chiu SM, Murphy ES, Lam M, Nieminen AL, Oleinick NL (2003) Domain-dependent photodamage to Bcl-2. A membrane anchorage region is needed to form the target of phthalocyanine photo-sensitization. J Biol Chem 278:2021–2029
Xue LY, Chiu SM, Fiebig A, Andrews DW, Oleinick NL (2003) Photodamage to multiple Bcl-xL isoforms by photodynamic therapy with the phthalocyanine photosensitizer pc 4. Oncogene 22:9197–9204
Wood SR, Holroyd JA, Brown SB (1997) The subcellular localization of Zn (II) phthalocyanines and their redistribution on exposure to light. J Photochem Photobiol B 65:397–402
Fabrics C, Valduga G, Miotto G, Borsetto L, Jori G, Garbisa S, Reddi E (2001) Photosensitization witn zinc(II) phthalocyanine as switch in the decision between apoptosis and necrosis. Cancer Res 61:7495–7502
Tynga IM, Houreld NN, Abrahamse H (2013) 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
Oniszczuk A, Wojtunik-Kulesza KA, Oniszczuk T, Kasprzak K (2016) The potential of photodynamic therapy (PDT)-experimental investigations and clinical use. Biomed Pharmacother 83:912–929
Lee SK, Forbes IJ, Betts WH (1984) Oxygen dependency of photocytotoxicity with hemtoporphyrin derivative. Photochem Photobiol 39:631–634
Moan J, Sommer S (1985) Oxygen dependence of the photosensitizing effect of hematoporphyrin derivative in NHIK-3025 cells. Cancer Res 45:1608–1610
Henderson BW, Fingar VH (1987) Relationship of tumor hypoxia and response to photodynamic treatment in an experimental mouse tumor. Cancer Res 47:3110–3114
Chapman JD, Stobbe CC, Arnfield MR (1991) Oxygen dependency of tumor cell killing in vitro by light activated Photofrin II. Radiat Res 126:73–79
Daruwalla J, Christophi C (2006) Hyperbaric oxygen therapy for malignancy: a review. World J Surg 30:2112–2131
Ricci JE (2003) Caspase-mediated loss of mitochondrial function and generation ofreactive oxygen species during apoptosis. J Cell Biol 160:65–75
Cosentino K, García-Sáez AJ (2014) Mitochondrial alterations in apoptosis. Chem Phys Lipids 181:62–75
Zorova LD, Popkov VA, Plotnikov EY, Silachev DN, Pevzner IB, Jankauskas SS, Babenko VA, Zorov SD, Balakireva AV, Juhaszova M, Sollott SJ, Zorov DB (2018) Mitochondrial membrane potential. Anal Biochem 552:50–59
Ly JD, Grubb DR, Lawen A (2003) The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis 8:115–128
Izyumov DS, Avetisyan AV, Pletjushkina OY, Sakharov DV, Wirtz KW, Chernyak BV, Skulachev VP (2004) “Wages of fear”: transient threefold decrease in intracellular ATP level imposes apoptosis. Biochim Biophys Acta 1658:141–147
Hodgkinson N, Kruger CA, Mokwena M, Abrahamse H (2017) Cervical cancer cells (HeLa) response to photodynamic therapy using a zinc phthalocyanine photosensitizer. Photochem Photobiol B 177:32–38
We would like to thank American Journal Experts (http://aje.com) for proofreading our manuscript.
This work was supported by the grants from the Ministry of Education, Youth and Sports of the Czech Republic LO1304, LM2015062, European Regional Development Fund CZ.02.1.01/0.0/0.0/16_019/0000868.
Conflict of interest
All authors declare that they have no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
For this type of study, formal consent is not required.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Pola, M., Kolarova, H., Ruzicka, J. et al. Effects of zinc porphyrin and zinc phthalocyanine derivatives in photodynamic anticancer therapy under different partial pressures of oxygen in vitro. Invest New Drugs 39, 89–97 (2021). https://doi.org/10.1007/s10637-020-00990-7