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Inhibition of hypoxia-inducible factor 1 with acriflavine sensitizes hypoxic tumor cells to photodynamic therapy with zinc phthalocyanine-encapsulating cationic liposomes

Photodynamic therapy (PDT) is a tumor treatment modality in which a tumorlocalized photosensitizer is excited with light, which results in local production of reactive oxygen species, destruction of tumor vasculature, tumor hypoxia, tumor cell death, and induction of an anti-tumor immune response. H... Full description

Journal Title: Nano Research 2016, Vol.9(6), pp.1639-1662
Main Author: Broekgaarden, Mans
Other Authors: Weijer, Ruud , Krekorian, Massis , IJssel, Bas , Kos, Milan , Alles, Lindy , Wijk, Albert , Bikadi, Zsolt , Hazai, Eszter , Gulik, Thomas , Heger, Michal
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 1998-0124 ; E-ISSN: 1998-0000 ; DOI: 10.1007/s12274-016-1059-0
Link: http://dx.doi.org/10.1007/s12274-016-1059-0
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recordid: springer_jour10.1007/s12274-016-1059-0
title: Inhibition of hypoxia-inducible factor 1 with acriflavine sensitizes hypoxic tumor cells to photodynamic therapy with zinc phthalocyanine-encapsulating cationic liposomes
format: Article
creator:
  • Broekgaarden, Mans
  • Weijer, Ruud
  • Krekorian, Massis
  • IJssel, Bas
  • Kos, Milan
  • Alles, Lindy
  • Wijk, Albert
  • Bikadi, Zsolt
  • Hazai, Eszter
  • Gulik, Thomas
  • Heger, Michal
subjects:
  • cancer therapy
  • confocal microscopy
  • drug delivery system
  • glucose metabolism
  • hypoxia
ispartof: Nano Research, 2016, Vol.9(6), pp.1639-1662
description: Photodynamic therapy (PDT) is a tumor treatment modality in which a tumorlocalized photosensitizer is excited with light, which results in local production of reactive oxygen species, destruction of tumor vasculature, tumor hypoxia, tumor cell death, and induction of an anti-tumor immune response. However, pre-existing tumor hypoxia may desensitize tumors to PDT by activating the hypoxia-inducible factor 1 (HIF-1) survival pathway. Therefore, we hypothesized that inhibition of HIF-1 with acriflavine (ACF) would exacerbate cell death in human epidermoid carcinoma (A431) cells. PDT of A431 tumor cells was performed using newly developed and optimized PEGylated cationic liposomes containing the photosensitizer zinc phthalocyanine (ZnPC). Molecular docking revealed that ACF binds to the dimerization domain of HIF-1α, and confocal microscopy confirmed translocation of ACF from the cytosol to the nucleus under hypoxia. HIF-1 was stabilized in hypoxic, but not normoxic, A431 cells following PDT. Inhibition of HIF-1 with ACF increased the extent of PDT-induced cell death under hypoxic conditions and reduced the expression of the HIF-1 target genes VEGF, PTGS2 , and EDN1 . Moreover, co-encapsulation of ACF in the aqueous core of ZnPC-containing liposomes yielded an adjuvant effect on PDT efficacy that was comparable to non-encapsulated ACF. In conclusion, HIF-1 contributes to A431 tumor cell survival following PDT with liposomal ZnPC. Inhibition of HIF-1 with free or liposomal ACF improves PDT efficacy.
language: eng
source:
identifier: ISSN: 1998-0124 ; E-ISSN: 1998-0000 ; DOI: 10.1007/s12274-016-1059-0
fulltext: fulltext
issn:
  • 1998-0000
  • 19980000
  • 1998-0124
  • 19980124
url: Link


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titleInhibition of hypoxia-inducible factor 1 with acriflavine sensitizes hypoxic tumor cells to photodynamic therapy with zinc phthalocyanine-encapsulating cationic liposomes
creatorBroekgaarden, Mans ; Weijer, Ruud ; Krekorian, Massis ; IJssel, Bas ; Kos, Milan ; Alles, Lindy ; Wijk, Albert ; Bikadi, Zsolt ; Hazai, Eszter ; Gulik, Thomas ; Heger, Michal
ispartofNano Research, 2016, Vol.9(6), pp.1639-1662
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subjectcancer therapy ; confocal microscopy ; drug delivery system ; glucose metabolism ; hypoxia
descriptionPhotodynamic therapy (PDT) is a tumor treatment modality in which a tumorlocalized photosensitizer is excited with light, which results in local production of reactive oxygen species, destruction of tumor vasculature, tumor hypoxia, tumor cell death, and induction of an anti-tumor immune response. However, pre-existing tumor hypoxia may desensitize tumors to PDT by activating the hypoxia-inducible factor 1 (HIF-1) survival pathway. Therefore, we hypothesized that inhibition of HIF-1 with acriflavine (ACF) would exacerbate cell death in human epidermoid carcinoma (A431) cells. PDT of A431 tumor cells was performed using newly developed and optimized PEGylated cationic liposomes containing the photosensitizer zinc phthalocyanine (ZnPC). Molecular docking revealed that ACF binds to the dimerization domain of HIF-1α, and confocal microscopy confirmed translocation of ACF from the cytosol to the nucleus under hypoxia. HIF-1 was stabilized in hypoxic, but not normoxic, A431 cells following PDT. Inhibition of HIF-1 with ACF increased the extent of PDT-induced cell death under hypoxic conditions and reduced the expression of the HIF-1 target genes VEGF, PTGS2 , and EDN1 . Moreover, co-encapsulation of ACF in the aqueous core of ZnPC-containing liposomes yielded an adjuvant effect on PDT efficacy that was comparable to non-encapsulated ACF. In conclusion, HIF-1 contributes to A431 tumor cell survival following PDT with liposomal ZnPC. Inhibition of HIF-1 with free or liposomal ACF improves PDT efficacy.
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titleInhibition of hypoxia-inducible factor 1 with acriflavine sensitizes hypoxic tumor cells to photodynamic therapy with zinc phthalocyanine-encapsulating cationic liposomes
descriptionPhotodynamic therapy (PDT) is a tumor treatment modality in which a tumorlocalized photosensitizer is excited with light, which results in local production of reactive oxygen species, destruction of tumor vasculature, tumor hypoxia, tumor cell death, and induction of an anti-tumor immune response. However, pre-existing tumor hypoxia may desensitize tumors to PDT by activating the hypoxia-inducible factor 1 (HIF-1) survival pathway. Therefore, we hypothesized that inhibition of HIF-1 with acriflavine (ACF) would exacerbate cell death in human epidermoid carcinoma (A431) cells. PDT of A431 tumor cells was performed using newly developed and optimized PEGylated cationic liposomes containing the photosensitizer zinc phthalocyanine (ZnPC). Molecular docking revealed that ACF binds to the dimerization domain of HIF-1α, and confocal microscopy confirmed translocation of ACF from the cytosol to the nucleus under hypoxia. HIF-1 was stabilized in hypoxic, but not normoxic, A431 cells following PDT. Inhibition of HIF-1 with ACF increased the extent of PDT-induced cell death under hypoxic conditions and reduced the expression of the HIF-1 target genes VEGF, PTGS2 , and EDN1 . Moreover, co-encapsulation of ACF in the aqueous core of ZnPC-containing liposomes yielded an adjuvant effect on PDT efficacy that was comparable to non-encapsulated ACF. In conclusion, HIF-1 contributes to A431 tumor cell survival following PDT with liposomal ZnPC. Inhibition of HIF-1 with free or liposomal ACF improves PDT efficacy.
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abstractPhotodynamic therapy (PDT) is a tumor treatment modality in which a tumorlocalized photosensitizer is excited with light, which results in local production of reactive oxygen species, destruction of tumor vasculature, tumor hypoxia, tumor cell death, and induction of an anti-tumor immune response. However, pre-existing tumor hypoxia may desensitize tumors to PDT by activating the hypoxia-inducible factor 1 (HIF-1) survival pathway. Therefore, we hypothesized that inhibition of HIF-1 with acriflavine (ACF) would exacerbate cell death in human epidermoid carcinoma (A431) cells. PDT of A431 tumor cells was performed using newly developed and optimized PEGylated cationic liposomes containing the photosensitizer zinc phthalocyanine (ZnPC). Molecular docking revealed that ACF binds to the dimerization domain of HIF-1α, and confocal microscopy confirmed translocation of ACF from the cytosol to the nucleus under hypoxia. HIF-1 was stabilized in hypoxic, but not normoxic, A431 cells following PDT. Inhibition of HIF-1 with ACF increased the extent of PDT-induced cell death under hypoxic conditions and reduced the expression of the HIF-1 target genes VEGF, PTGS2 , and EDN1 . Moreover, co-encapsulation of ACF in the aqueous core of ZnPC-containing liposomes yielded an adjuvant effect on PDT efficacy that was comparable to non-encapsulated ACF. In conclusion, HIF-1 contributes to A431 tumor cell survival following PDT with liposomal ZnPC. Inhibition of HIF-1 with free or liposomal ACF improves PDT efficacy.
copBeijing
pubTsinghua University Press
doi10.1007/s12274-016-1059-0
pages1639-1662
date2016-06