Selenium enhances photodynamic therapy of C-phycocyanin against lung cancer via dual regulation of cytotoxicity and antioxidant activity

As a natural photosensitizer, phycocyanin (PC) has high efficiency and uses low-intensity irradiation. To enhance the photodynamic therapy (PDT) of PC, we extract selenium-enriched phycocyanin (Se-PC) from Se-enriched Spirulina platensis and examine the synergistic effect of PC combined with selenium against lung tumors. In vitro experiments reveal that Se-PC PDT more efficiently reduce the survival rate of mouse lung cancer cells (LLC cell line) than PC PDT treatment by increasing the level of ROS and decreasing the level of GPx4, which is confirmed by the Chou-Talalay assay. In vivo imaging system analysis reveal that tumor volume is more markedly decreased in both the Se-PC PDT and PC PDT plus Na 2SeO 3 groups than in the PC PDT group, with inhibition rates reaching 90.4%, 68.3% and 53.1%, respectively, after irradiation with 100 J/cm 2 laser light at 630 nm. In normal tissues, Se-PC promotes the synthesis of antioxidant enzymes and the immune response by the IL-6/TNF-α pathway against tumor proliferation and metastasis. Using Se-PC as a photosensitizer in tumors, apoptosis and pyroptosis are the primary types of cell death switched by Caspases-1/3/9, which is confirmed by TEM. Based on the transcriptome analysis, Se-PC PDT treatment inhibits angiogenesis, regulates inflammation by the HIF-1, NF-κB and TGF-β signaling pathways and dilutes tumor metabolism by reducing the synthesis of glucose transporters and transferrin. Compared to PC PDT, Se-PC increases the expression levels of some chemokines in the tumor niche, which recruits inflammatory cells to enhance the immune response. Our study may provide evidence for Se-PC as an effective photosensitizer to treat lung cancer. Keywords: PDT; ROS; antioxidant; phycocyanin; selenium.