Article Title

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

Authors

Mans Broekgaarden, Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Ruud Weijer, Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Massis Krekorian, Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Bas van den IJssel, Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Milan Kos, Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Lindy K. Alles, Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Albert C. van Wijk, Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Zsolt Bikadi, Virtua Drug Ltd., Csalogany 4C, H-1015, Budapest, Hungary
Eszter Hazai, Virtua Drug Ltd., Csalogany 4C, H-1015, Budapest, Hungary
Thomas M. van Gulik, Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Michal Heger, Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

Keywords

cancer therapy, confocal microscopy, drug delivery system, glucose metabolism, hypoxia

Abstract

Photodynamic therapy (PDT) is a tumor treatment modality in which a tumorlocalizedphotosensitizer is excited with light, which results in local productionof 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 thehypoxia-inducible factor 1 (HIF-1) survival pathway. Therefore, we hypothesizedthat inhibition of HIF-1 with acriflavine (ACF) would exacerbate cell death inhuman epidermoid carcinoma (A431) cells. PDT of A431 tumor cells was performedusing newly developed and optimized PEGylated cationic liposomescontaining the photosensitizer zinc phthalocyanine (ZnPC). Molecular dockingrevealed that ACF binds to the dimerization domain of HIF-1α, and confocalmicroscopy confirmed translocation of ACF from the cytosol to the nucleusunder hypoxia. HIF-1 was stabilized in hypoxic, but not normoxic, A431 cellsfollowing PDT. Inhibition of HIF-1 with ACF increased the extent of PDT-inducedcell death under hypoxic conditions and reduced the expression of the HIF-1target genes VEGF, PTGS2, and EDN1. Moreover, co-encapsulation of ACF in theaqueous core of ZnPC-containing liposomes yielded an adjuvant effect on PDTefficacy that was comparable to non-encapsulated ACF. In conclusion, HIF-1contributes to A431 tumor cell survival following PDT with liposomal ZnPC.Inhibition of HIF-1 with free or liposomal ACF improves PDT efficacy.

Graphical Abstract

DOI

https://doi.org/10.1007/s12274-016-1059-0

Publisher

Tsinghua University Press

Recommended Citation

Mans Broekgaarden,Ruud Weijer,Massis Krekorian,Bas van den IJssel,Milan Kos,Lindy K. Alles,Albert C. van Wijk,Zsolt Bikadi,Eszter Hazai,Thomas M. van Gulik,Michal Heger, Inhibition of hypoxia-inducible factor 1 with acriflavine sensitizes hypoxic tumor cells to photodynamic therapy with zinc phthalocyanine-encapsulating cationic liposomes. NanoRes.2016, 9(6): 1639–1662