Mechanisms of Resistance to Photodynamic Therapy (PDT) in Vulvar Cancer
Photodynamic therapy (PDT) is a valuable treatment method for vulvar intraepithelial neoplasia (VIN). It allows for the treatment of a multifocal disease with minimal tissue destruction. 5-Aminolevulinic acid (5-ALA) is the most commonly used prodrug, which is converted in the heme pathway to protop...
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MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/8/4117 |
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| author | Beata Joanna Mossakowska Somayeh Shahmoradi Ghahe Dominik Cysewski Anna Fabisiewicz Barbara Tudek Janusz Aleksander Siedlecki |
| author_facet | Beata Joanna Mossakowska Somayeh Shahmoradi Ghahe Dominik Cysewski Anna Fabisiewicz Barbara Tudek Janusz Aleksander Siedlecki |
| author_sort | Beata Joanna Mossakowska |
| collection | DOAJ |
| description | Photodynamic therapy (PDT) is a valuable treatment method for vulvar intraepithelial neoplasia (VIN). It allows for the treatment of a multifocal disease with minimal tissue destruction. 5-Aminolevulinic acid (5-ALA) is the most commonly used prodrug, which is converted in the heme pathway to protoporphyrin IX (PpIX), an actual photosensitizer (PS). Unfortunately, not all patients treated with PDT undergo complete remission. The main cause of their failure is resistance to anticancer therapy. In many cancers, resistance to various anticancer treatments is correlated with increased activity of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1). Enhanced activity of drug pumps may also affect the effectiveness of therapy. To investigate whether multidrug resistance mechanisms underlie PDT resistance in VIN, porphyrins were isolated from sensitive and resistant vulvar cancer cells and their culture media. APE1 activity was measured, and survival assay after PDT combined with APE1 inhibitor was performed. Our results revealed that resistant cells accumulated and effluxed less porphyrins than sensitive cells, and in response to PDT, resistant cells increased APE1 activity. Moreover, PDT combined with inhibition of APE1 significantly decreased the survival of PDT-resistant cells. This means that resistance to PDT in vulvar cancer may be the result of alterations in the heme synthesis pathway. Moreover, increased APE1 activity may be essential for the repair of PDT-mediated DNA damage, and inhibition of APE1 activity may increase the efficacy of PDT. |
| first_indexed | 2024-03-09T13:33:58Z |
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| id | doaj.art-092b855c87444b6daeb9b06c979dffef |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T13:33:58Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-092b855c87444b6daeb9b06c979dffef2023-11-30T21:14:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01238411710.3390/ijms23084117Mechanisms of Resistance to Photodynamic Therapy (PDT) in Vulvar CancerBeata Joanna Mossakowska0Somayeh Shahmoradi Ghahe1Dominik Cysewski2Anna Fabisiewicz3Barbara Tudek4Janusz Aleksander Siedlecki5Department of Molecular and Translational Oncology, Maria Skłodowska-Curie National Research Institute of Oncology, Roentgena 5, 02-781 Warsaw, PolandInstitute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warsaw, PolandInstitute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warsaw, PolandDepartment of Molecular and Translational Oncology, Maria Skłodowska-Curie National Research Institute of Oncology, Roentgena 5, 02-781 Warsaw, PolandInstitute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warsaw, PolandDepartment of Molecular and Translational Oncology, Maria Skłodowska-Curie National Research Institute of Oncology, Roentgena 5, 02-781 Warsaw, PolandPhotodynamic therapy (PDT) is a valuable treatment method for vulvar intraepithelial neoplasia (VIN). It allows for the treatment of a multifocal disease with minimal tissue destruction. 5-Aminolevulinic acid (5-ALA) is the most commonly used prodrug, which is converted in the heme pathway to protoporphyrin IX (PpIX), an actual photosensitizer (PS). Unfortunately, not all patients treated with PDT undergo complete remission. The main cause of their failure is resistance to anticancer therapy. In many cancers, resistance to various anticancer treatments is correlated with increased activity of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1). Enhanced activity of drug pumps may also affect the effectiveness of therapy. To investigate whether multidrug resistance mechanisms underlie PDT resistance in VIN, porphyrins were isolated from sensitive and resistant vulvar cancer cells and their culture media. APE1 activity was measured, and survival assay after PDT combined with APE1 inhibitor was performed. Our results revealed that resistant cells accumulated and effluxed less porphyrins than sensitive cells, and in response to PDT, resistant cells increased APE1 activity. Moreover, PDT combined with inhibition of APE1 significantly decreased the survival of PDT-resistant cells. This means that resistance to PDT in vulvar cancer may be the result of alterations in the heme synthesis pathway. Moreover, increased APE1 activity may be essential for the repair of PDT-mediated DNA damage, and inhibition of APE1 activity may increase the efficacy of PDT.https://www.mdpi.com/1422-0067/23/8/4117photodynamic therapyphotosensitizerprotoporphyrin IXheme metabolismmultidrug resistanceDNA repair |
| spellingShingle | Beata Joanna Mossakowska Somayeh Shahmoradi Ghahe Dominik Cysewski Anna Fabisiewicz Barbara Tudek Janusz Aleksander Siedlecki Mechanisms of Resistance to Photodynamic Therapy (PDT) in Vulvar Cancer International Journal of Molecular Sciences photodynamic therapy photosensitizer protoporphyrin IX heme metabolism multidrug resistance DNA repair |
| title | Mechanisms of Resistance to Photodynamic Therapy (PDT) in Vulvar Cancer |
| title_full | Mechanisms of Resistance to Photodynamic Therapy (PDT) in Vulvar Cancer |
| title_fullStr | Mechanisms of Resistance to Photodynamic Therapy (PDT) in Vulvar Cancer |
| title_full_unstemmed | Mechanisms of Resistance to Photodynamic Therapy (PDT) in Vulvar Cancer |
| title_short | Mechanisms of Resistance to Photodynamic Therapy (PDT) in Vulvar Cancer |
| title_sort | mechanisms of resistance to photodynamic therapy pdt in vulvar cancer |
| topic | photodynamic therapy photosensitizer protoporphyrin IX heme metabolism multidrug resistance DNA repair |
| url | https://www.mdpi.com/1422-0067/23/8/4117 |
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