Project description:The efficacy of photodynamic therapy for treating premalignant and malignant tumors is often limited by the emerging resistant tumor cells. We have developed experimental model systems to study the mechanisms associated with resistance to photodynamic therapy induced by structurally similar photosensitizers (two novel porphyrin-based photosensitizers and temoporfin) in mouse mammary carcinoma cell line 4T1. Photodynamic therapy resistant clones were obtained in vitro by exposure to constant photosensitizer concentration and irradiation with increasing light doses.
Project description:Differentiation therapy with all-trans retinoic acid (ATRA) is well established for acute promyelocytic leukemia (APL). However, the narrow application and tolerance development of ATRA remain to be improved. In this study, we challenged glycosylation inhibitor to obtain better efficiency than ATRA alone. As a result, we found that the combination of fucosylation inhibitor 6-alkynylfucose (6AF) with ATRA have profound effect for differentiation, shown by expression changes of differentiation markers CD11b, CD11c, with significant morphological change in NB4 and HL-60 cells. From lectin blot assay, we found that ATRA or 6AF alone could decrease core fucosylation, the combination of these two agents efficiently decreases the expression of core fucosylation. To reveal molecular mechanisms to reveal 6AF effect for ATRA induced differentiation, we next performed microarray analysis using NB4 cells. From pathway analysis using DAVID software, we found that C-type lectin receptor (CLR) signaling pathway was enriched as high significance. From real time PCR analysis, using NB4 and HL-60 cells, FcRI, CLEC6A, CASP1, IL-1, EGR2/3, the components of CLR, and Akt, were indeed upregulated by 6AF in ATRA induced differentiation. These suggest that the involvement of CLR signaling pathway in 6AF effect of ATRA induced differentiation.
Project description:We used selenium as a photodynamic anti-tumor synergist of phycocyanin to explore its inhibitory effect on lung cancer and its molecular mechanism in vitro. First of all, we used LLC-luc mouse lung cancer cells to establish a tumor-bearing model. Selenium-enriched phycocyanin was injected next to the tumor. When it was absorbed by the tumor tissue, the tumor site was irradiated by a 620nm wavelength laser. The changes in tumor size were monitored in real-time and the physiological indexes of mice were measured. It was found that selenium phycocyanin photodynamic therapy could enhance the inhibitory effect of tumors and improve the level of antioxidation in tumor-bearing mice. In addition, the pathological section observation and electron microscope microstructure analysis of the tumor tissue showed that the effect of the selenium-enriched phycocyanin photodynamic treatment group was more significant. At the same time, the tumor tissue transcriptional group sequencing analysis and qRT-PCR verification analysis showed that selenium-enriched phycocyanin photodynamic treatment group could reduce the expression of Mmp13, Serpine1, Vegfa, and Ppbp genes inhibit tumor cell metastasis and proliferation, up-regulate the expression of Ccl2, Ccl3, Cxcl2 and down-regulate the expression of Ccl24 chemokine, and promote tumor local immunity. Our results show that selenium phycocyanin photodynamic therapy plays an anti-tumor effect by promoting tumor cell apoptosis, reducing inflammation, and promoting tumor immunity.
Project description:All-trans retinoic acid (atRA) regulates gene expression and is used to treat acute promyelocytic leukemia. Attempts to use atRA for breast cancer treatment without a stratification strategy have resulted in limited overall effectiveness. To identify biomarkers for the treatment of triple-negative breast cancer (TNBC) with atRA, we characterized the effects of atRA on the tumor growth of 13 TNBC cell lines. This resulted in a range of tumor growth effects that was not predictable based on the levels of retinoid signaling molecules and transcriptional responses that were mostly independent of retinoic acid response elements. Given the importance of DNA methylation in regulating gene expression, we hypothesized that differential DNA methylation could predict the response of TNBCs to atRA. We identified over 1400 CpG sites that were differentially methylated between atRA resistant and sensitive cell lines. These CpG sites predicted the response of four TNBC patient-derived xenografts to atRA treatment and we utilized these xenografts to refine the profile to 6 CpGs. We identify as many as 17% of TNBC patients who could benefit from atRA treatment. These data illustrate that differential DNA methylation of specific sites may predict the response of patient tumors to atRA treatment.
Project description:All-trans retinoic acid (atRA) regulates gene expression and is used to treat acute promyelocytic leukemia. Attempts to use atRA for breast cancer treatment without a stratification strategy have resulted in limited overall effectiveness. To identify biomarkers for the treatment of triple-negative breast cancer (TNBC) with atRA, we characterized the effects of atRA on the tumor growth of 13 TNBC cell lines. This resulted in a range of tumor growth effects that was not predictable based on the levels of retinoid signaling molecules and transcriptional responses that were mostly independent of retinoic acid response elements. Given the importance of DNA methylation in regulating gene expression, we hypothesized that differential DNA methylation could predict the response of TNBCs to atRA. We identified over 1400 CpG sites that were differentially methylated between atRA resistant and sensitive cell lines. These CpG sites predicted the response of four TNBC patient-derived xenografts to atRA treatment and we utilized these xenografts to refine the profile to 6 CpGs. We identify as many as 17% of TNBC patients who could benefit from atRA treatment. These data illustrate that differential DNA methylation of specific sites may predict the response of patient tumors to atRA treatment. This study characterizes the gene expression of 2 triple-negative patient-derived breast cancer xenografts