![]() Radiation therapy, most used in cancer treatment, induces a plethora of DNA lesions that affect DNA integrity and, in-turn, DNA replication. ![]() ![]() So whilst replication stress induces genomic instability and tumorigenesis, the replication stress response exhibits a unique cancer-specific vulnerability that can be targeted to induce catastrophic cell proliferation. Most malignant tumors sustain persistent proliferation and tolerate replication stress via increasing reliance to the replication stress response. Overall, DR-SIP may have the potential to elicit an immune response as an ICD inducer.ĭNA replication is a process fundamental in all living organisms in which deregulation, known as replication stress, often leads to genomic instability, a hallmark of cancer. When intravenously administered to tumor-bearing mice, DR-SIP remarkably inhibits tumor growth compared with DOX alone. In addition, DR-SIP contributes to the maturation of dendritic cells by promoting the release of damage-associated molecular patterns (DAMPs) from cancer cells. Interestingly, when treated with 4T1 cancer cells, DOX-encapsulated R–SIP (DR-SIP) induces the phosphorylation of eukaryotic translation initiation factor 2α and overexpression of ecto-calreticulin, resulting in endoplasmic reticulum-associated ICD. Owing to its amphiphilic nature, R–SIP self-assemble into nano-sized particles under aqueous conditions, and DOX is efficiently encapsulated inside the nanoparticles by a simple dialysis method. To enhance the immunogenicity of DOX, we prepare a reactive oxygen species (ROS)-responsive self-immolative polymer (R–SIP) that can efficiently destroy redox homeostasis via self-immolation-mediated glutathione depletion in cancer cells. However, its extended application as an ICD inducer has been limited owing to poor antigenicity and inefficient adjuvanticity. PDT group (gray bars), Two-Way ANOVA Bonferroni post-test.ĭoxorubicin (DOX), widely used as an anticancer drug, is considered an immunogenic cell death (ICD) inducer that enhances cancer immunotherapy. Data are mean ± SEM of three independent experiments. Quantification of mRNA expression of IFN-1-α (right) and IFN-β (left) was performed 1, 5, and 14 h after treatment by RTqPCR and normalized with respect to the non-treated control (dotted line: 1). (D) B16-OVA cells were subjected to high dose PDT (Me-ALA 0.3 mM + 0.5 J/cm 2 ) or doxorubicin (30 µM). (C) Viable cells (Annexin V − /PI − ), undergoing (early) apoptotic cells (Annexin V + /PI − ) and dead, necrotic or late (end-stage) apoptotic cells (Annexin V + /PI + ) were quantified using FlowJo 10.0.7 software. The data generated by flow cytometry were plotted in two-dimensional dot plots in which PI is represented vs. ![]() (B) Type of cell death was evaluated using Annexin V/PI staining by flow cytometry. control group (untreated cells), One-Way ANOVA Bonferroni post-test. Quantification of mRNA expression of IFN-1α (right) and IFN-β (left) was performed 5 h after treatment by RTqPCR and normalized with respect to the non-treated control (dotted line: 1). (A) B16-OVA cells were incubated with Me-ALA (0.1, 0.2, and 0.3 mM) for 4 h and then were irradiated with visible light (0.5 J/cm 2 ). | Photodynamic therapy as a novel inductor of IFN-1 expression on melanoma cells.
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