Low-power photodynamic therapy induces survival signaling in perihilar cholangiocarcinoma cells

Weijer, Ruud; Broekgaarden, Mans; Golen, Rowan F. van; Bulle, Esther; Nieuwenhuis, E. E. S.; Jongejan, Aldo; Moerland, Perry D.; Kampen, Antoine H. C. van; Gulik, Thomas M. van; Heger, Michal

doi:10.1186/s12885-015-1994-2

Cited by 38 publications

(31 citation statements)

References 51 publications

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“…PDT also led to the differential regulation of HIF-1-regulated genes, including VEGF, PTGS2, SERPINE1, HMOX1 , and BIRC5 . Consistent with these results, it was recently demonstrated that SK-ChA-1 cells subjected to sublethal PDT with neutral ZnPC-encapsulating liposomes significantly upregulated HIF-1-associated genes 90 minutes post-PDT [ 52 ]. Altogether, these findings attest that HIF-1α is activated following PDT and that this transcription factor constitutes an important therapeutic target, particularly in light of the fact that HIF-1 regulates biological processes that are important in PDT, such as glycolysis, angiogenesis, and survival [ 10 ].…”

Section: Discussionsupporting

confidence: 71%

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Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy

et al. 2015

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Background: Photodynamic therapy (PDT) induces tumor cell death by oxidative stress and hypoxia but also survival signaling through activation of hypoxia-inducible factor 1 (HIF-1). Since perihilar cholangiocarcinomas are relatively recalcitrant to PDT, the aims were to (1) determine the expression levels of HIF-1-associated proteins in human perihilar cholangiocarcinomas, (2) investigate the role of HIF-1 in PDT-treated human perihilar cholangiocarcinoma cells, and (3) determine whether HIF-1 inhibition reduces survival signaling and enhances PDT efficacy.Results: Increased expression of VEGF, CD105, CD31/Ki-67, and GLUT-1 was confirmed in human perihilar cholangiocarcinomas. PDT with liposome-delivered zinc phthalocyanine caused HIF-1α stabilization in SK-ChA-1 cells and increased transcription of HIF-1α downstream genes. Acriflavine was taken up by SK-ChA-1 cells and translocated to the nucleus under hypoxic conditions. Importantly, pretreatment of SK-ChA-1 cells with acriflavine enhanced PDT efficacy via inhibition of HIF-1 and topoisomerases I and II.Methods: The expression of VEGF, CD105, CD31/Ki-67, and GLUT-1 was determined by immunohistochemistry in human perihilar cholangiocarcinomas. In addition, the response of human perihilar cholangiocarcinoma (SK-ChA-1) cells to PDT with liposome-delivered zinc phthalocyanine was investigated under both normoxic and hypoxic conditions. Acriflavine, a HIF-1α/HIF-1β dimerization inhibitor and a potential dual topoisomerase I/II inhibitor, was evaluated for its adjuvant effect on PDT efficacy.Conclusions: HIF-1, which is activated in human hilar cholangiocarcinomas, contributes to tumor cell survival following PDT in vitro. Combining PDT with acriflavine pretreatment improves PDT efficacy in cultured cells and therefore warrants further preclinical validation for therapy-recalcitrant perihilar cholangiocarcinomas.

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Section: Discussionsupporting

confidence: 71%

“…RNA was quantified and analyzed with a Nanodrop 2000 UV-VIS spectrophotometer (Thermo Scientific). cDNA synthesis and RT-qPCR reactions were performed according to [ 52 ]. The primers that were used in this study are listed in Table S1 .…”

Section: Methodsmentioning

confidence: 99%

Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy

et al. 2015

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“…cDNA synthesis and qRT-PCR reactions were performed as described previously [16]. Primer sequences can be found in Table S3.…”

Section: Methodsmentioning

confidence: 99%

“…In light of this combined therapy and the broader scope of applicability of the PDT platform technology, it is imperative to map post-PDT survival pathways [ 9 ] for every liposomal formulation so as to identify druggable targets beyond those already tested [ 9 ]. So far we have mapped PDT-activated survival pathways with respect to the interstitially targeted ZnPC-liposomes [ 16 ], but not yet for the endothelium- and tumor cell-targeting liposomes.…”

Section: Introductionmentioning

confidence: 99%

Multi-OMIC profiling of survival and metabolic signaling networks in cells subjected to photodynamic therapy

Weijer

Clavier

Zaal

et al. 2016

Cell. Mol. Life Sci.

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Photodynamic therapy (PDT) is an established palliative treatment for perihilar cholangiocarcinoma that is clinically promising. However, tumors tend to regrow after PDT, which may result from the PDT-induced activation of survival pathways in sublethally afflicted tumor cells. In this study, tumor-comprising cells (i.e., vascular endothelial cells, macrophages, perihilar cholangiocarcinoma cells, and EGFR-overexpressing epidermoid cancer cells) were treated with the photosensitizer zinc phthalocyanine that was encapsulated in cationic liposomes (ZPCLs). The post-PDT survival pathways and metabolism were studied following sublethal (LC50) and supralethal (LC90) PDT. Sublethal PDT induced survival signaling in perihilar cholangiocarcinoma (SK-ChA-1) cells via mainly HIF-1-, NF-кB-, AP-1-, and heat shock factor (HSF)-mediated pathways. In contrast, supralethal PDT damage was associated with a dampened survival response. PDT-subjected SK-ChA-1 cells downregulated proteins associated with EGFR signaling, particularly at LC90. PDT also affected various components of glycolysis and the tricarboxylic acid cycle as well as metabolites involved in redox signaling. In conclusion, sublethal PDT activates multiple pathways in tumor-associated cell types that transcriptionally regulate cell survival, proliferation, energy metabolism, detoxification, inflammation/angiogenesis, and metastasis. Accordingly, tumor cells sublethally afflicted by PDT are a major therapeutic culprit. Our multi-omic analysis further unveiled multiple druggable targets for pharmacological co-intervention.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-016-2401-0) contains supplementary material, which is available to authorized users.

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“…Lastly, research is beginning to focus in the development of fourth-generation PS (i.e., a second-generation PS encapsulated in a NP delivery system—making it a third-generation PS, with a co-encapsulated small-molecular inhibitor capable of blocking tumour survival pathways post PDT treatment in order to improve its overall efficacy in clinical settings and so halt possible tumour reoccurrence [ 18 , 19 ]. At this stage, combination treatments with respect to PDT and inhibitors in clinical setting are limited to the treatment of macular degeneration, in which case vascular endothelial growth factors (VEGFs) inhibitors are employed to deter neovascularization of tumours [ 18 , 19 ].…”

Section: Photosensitisersmentioning

confidence: 99%

Utilisation of Targeted Nanoparticle Photosensitiser Drug Delivery Systems for the Enhancement of Photodynamic Therapy

Kruger

Abrahamse

2018

Molecules

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The cancer incidence world-wide has caused an increase in the demand for effective forms of treatment. One unconventional form of treatment for cancer is photodynamic therapy (PDT). PDT has 3 fundamental factors, namely a photosensitiser (PS) drug, light and oxygen. When a PS drug is administered to a patient, it can either passively or actively accumulate within a tumour site and once exposed to a specific wavelength of light, it is excited to produce reactive oxygen species (ROS), resulting in tumour destruction. However, the efficacy of ROS generation for tumour damage is highly dependent on the uptake of the PS in tumour cells. Thus, PS selective/targeted uptake and delivery in tumour cells is a crucial factor in PDT cancer drug absorption studies. Generally, within non-targeted drug delivery mechanisms, only minor amounts of PS are able to passively accumulate in tumour sites (due to the enhanced permeability and retention (EPR) effect) and the remainder distributes into healthy tissues, causing unwanted side effects and poor treatment prognosis. Thus, to improve the efficacy of PDT cancer treatment, research is currently focused on the development of specific receptor-based PS-nanocarrier platform drugs, which promote the active uptake and absorption of PS drugs in tumour sites only, avoiding unwanted side effects, as well as treatment enhancement. Therefore, the aim of this review paper is to focus on current actively targeted or passively delivered PS nanoparticle drug delivery systems, that have been previously investigated for the PDT treatment of cancer and so to deduce their overall efficacy and recent advancements.

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Low-power photodynamic therapy induces survival signaling in perihilar cholangiocarcinoma cells

Cited by 38 publications

References 51 publications

Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy

Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy

Multi-OMIC profiling of survival and metabolic signaling networks in cells subjected to photodynamic therapy

Utilisation of Targeted Nanoparticle Photosensitiser Drug Delivery Systems for the Enhancement of Photodynamic Therapy

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