摘要
Photodynamic therapy （PDT） is a tumor treatment modality in which a tumor- localized 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 per- formed 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-la, 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.
Photodynamic therapy （PDT） is a tumor treatment modality in which a tumor- localized 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 per- formed 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-la, 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.
