Caveolin-1 Modulation Increases Efficacy of a Galacto-Conjugated Phthalocyanine in Bladder Cancer Cells Resistant to Photodynamic Therapy
- 27 April 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Molecular Pharmaceutics
- Vol. 17 (6), 2145-2154
- https://doi.org/10.1021/acs.molpharmaceut.0c00298
Abstract
Photodynamic Therapy (PDT) has demonstrated encouraging anticancer therapeutic results, but the current clinically approved photosensitizers (PSs) are not ideal in the treatment of bladder cancer. Conventional PSs have low selectivity to the bladder tumor tissue and induce toxicity or bystander effects on non-tumor urothelium. Previous studies demonstrated that the use of galactose-photosensitizer (PS) conjugates is a more selective method of delivering PDT-mediated toxicity due to their ability to recognize carbohydrate-binding domains overexpressed in bladder tumors. Using patient-derived bladder tumor specimens cultured ex vivo and bladder cancer cell lines with different PDT sensitivity, we find that a galactose-phthalocyanine (PcGal16) accumulates in bladder tumors expressing galactose-binding proteins and internalizes through an endocytic process. The endocytosis mechanism is cell line-dependent. In bladder cancer lines resistant to PDT, PcGal16 uptake occurs through a caveolae-mediated pathway. Depletion of caveolin-1 – the main structural protein of caveolae structures – in bladder cancer cells resistant to PDT increased the amount of sugar-binding proteins, i.e. GLUT1, at the cell membrane resulting in an improved PcGal16 uptake and PDT efficacy. These data show the potential of ex vivo cultures of bladder cancer, that ideally could mimic the original microenvironment, in screening galacto-PDT agents. Additionally, our studies demonstrate that PDT efficacy in bladder cancer depends on the endocytic mechanisms that regulate PS accumulation and internalization in cancer cells.Keywords
Funding Information
- European Regional Development Fund
- Funda??o para a Ci?ncia e a Tecnologia (FCT UID/NEU/04539/2019, FCT UID/QUI/00062/2019, FCT UID/QUI/0100/2019, PD/BD/52294/2013, POCI-01-0145-FEDER-007440)
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