Inhibition of hypoxia-inducible factor 1 with acriflavine sensitizes hypoxic tumor cells to photodynamic therapy with zinc phthalocyanine-encapsulating cationic liposomes
cancer therapy, confocal microscopy, drug delivery system, glucose metabolism, hypoxia
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.
Tsinghua University Press
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