Abstract
Photodynamic therapy (PDT), a promising treatment option for cancer, involves the activation of a photosensitizer (PS) by local irradiation with visible light. Excitation of the PS leads to a series of photochemical reactions and consequently the local generation of harmful reactive oxygen species (ROS) causing limited or none systemic defects. However, the development of resistance to this promising therapy has slowed down its translation into the clinical practice. Thus, there is an increase need in understanding of the molecular mechanism underlying resistance to PDT. Here, we aimed to examine whether a relationship exists between PDT outcome and ROS-involvement in the resistance mechanism in photosensitized cancer cells. In order to recapitulate tumor architecture of the respective original tumor, we developed a multicellular three-dimensional spheroid system comprising a normoxic periphery, surrounding a hypoxic core. Using Me-ALA, a prodrug of the PS PpIX, in human colorectal spheroids we demonstrate that HIF-1 transcriptional activity was strongly up-regulated and mediates PDT resistant phenotype. RNAi knockdown of HIF-1 impairs resistance to PDT. Oxidative stress-mediated activation of ERK1/2 followed PDT was involved on positive modulation of HIF-1 transcriptional activity after photodynamic treatment. ROS scavenging and MEK/ERK pathway inhibition abrogated the PDT-mediated HIF-1 upregulation. Together our data demonstrate that resistance to PDT is in part mediated by the activation of a ROS-ERK1/2-HIF-1 axis, thus, identifying novel therapeutic targets that could be used in combination with PDT.
Highlights
Photodynamic therapy (PDT) is an emerging antitumoral approach consisting in the administration of a photosensitizer (PS) followed by local irradiation with visible light of specific wavelength(s)
Spheroids were sensitized with Me-aminolevulinic acid (ALA)-induced Protoporphyrin IX (PpIX) and subsequently irradiated. Three dimensional (3D) cultures treated using the same photodynamic conditions than their 2D counterparts show less than 50% of cell death (Fig 1A)
HIF modulation of PDT resistance incubation time with Me-ALA. 3D cultures were generated from SW480 cells constitutively expressing GFP (SW480-G), which constitutively express Green fluorescent protein (GFP) to help identify viable cells (GFP+) [24]
Summary
Photodynamic therapy (PDT) is an emerging antitumoral approach consisting in the administration of a photosensitizer (PS) followed by local irradiation with visible light of specific wavelength(s). In the presence of oxygen molecules, the light illumination of PS can lead to a series of photochemical reactions and the generation of harmful reactive oxygen. HIF modulation of PDT resistance decision to publish, or preparation of the manuscript
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