Inhibition of NF-κB in Tumor Cells Exacerbates Immune Cell Activation Following Photodynamic Therapy

Broekgaarden, Mans; Kos, Milan; Jurg, Freek A.; Beek, Adriaan A. van; Gulik, Thomas M. van; Heger, Michal

doi:10.3390/ijms160819960

Cited by 21 publications

(18 citation statements)

References 65 publications

(107 reference statements)

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“…Corroboratively, treatment of A431 and SK-ChA-1 cells with the HIF-1 inhibitor acriflavine significantly improved PDT efficacy [ 11 , 13 ]. Similarly, it was shown in various studies that combined treatment comprising NF-кB inhibitors and PDT augmented therapeutic efficacy [ 35 , 58 , 59 ].…”

Section: Discussionmentioning

confidence: 82%

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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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Section: Discussionmentioning

confidence: 82%

“…This hyperactive state may in part have been caused by the fact that macrophages become activated upon exposure to dying cells and cell debris [60], including post-PDT [35]. The same pattern was observed for HUVEC cells, but in contrast to the tumor cell lines, only few differences were observed between the LC 50 and LC 90 groups.…”

Section: Discussionmentioning

confidence: 88%

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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“…263-265 Studies during which PDT was combined with inhibitors of the inflammatory response and immediate early stress responses have yielded non-coherent results, potentially owing to the dichotomous functions of these signaling pathways with respect to cell survival and cell death. 247, 266-268 …”

Section: Approaches To Manipulate Cancer Tissue Using Photochemistry mentioning

confidence: 99%

Photonanomedicine: a convergence of photodynamic therapy and nanotechnology

et al. 2016

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As clinical nanomedicine has emerged over the past two decades, phototherapeutic advancements using nanotechnology have also evolved and impacted disease management. Because of unique features attributable to the light activation process of molecules, photonanomedicine (PNM) holds significant promise as a personalized, image-guided therapeutic approach for cancer and non-cancer pathologies. The convergence of advanced photochemical therapies such as photodynamic therapy (PDT) and imaging modalities with sophisticated nanotechnologies is enabling the ongoing evolution of fundamental PNM formulations, such as Visudyne®, into progressive forward-looking platforms that integrate theranostics (therapeutics and diagnostics), molecular selectivity, the spatiotemporally controlled release of synergistic therapeutics, along with regulated, sustained drug dosing. Considering that the envisioned goal of these integrated platforms is proving to be realistic, this review will discuss how PNM has evolved over the years as a preclinical and clinical amalgamation of nanotechnology with PDT. The encouraging investigations that emphasize the potent synergy between photochemistry and nanotherapeutics, in addition to the growing realization of the value of these multi-faceted theranostic nanoplatforms, will assist in driving PNM formulations into mainstream oncological clinical practice as a necessary tool in the medical armamentarium.

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“…, a cell line derived from a type of cancer that is recalcitrant to different types of treatment. The photosensitizer used in this study was zinc phthalocyanine (ZnPC), a second-generation photosensitizer that was encapsulated in cationic liposomes designed to target tumor cells and tumor endothelium [ 35 , 36 ]. ACF was selected due to its selective inhibition of HIF-1 activation [ 37 ] and due to its clinical safety [ 38 ].…”

Section: Introductionmentioning

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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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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Inhibition of NF-κB in Tumor Cells Exacerbates Immune Cell Activation Following Photodynamic Therapy

Cited by 21 publications

References 65 publications

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

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

Photonanomedicine: a convergence of photodynamic therapy and nanotechnology

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

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