Down-regulation of ABCC11 protein (MRP8) in human breast cancer

Aim of this article is to investigate the expression of ABCC11 (MRP8) protein in normal breast tissue, and examine the difference in ABCC11 mRNA and protein expression between normal breast and breast cancer tissues taking into account ABCC11 genotype (a functional SNP, rs17822931) and estrogen receptor (ER) status

Nuclear Factor-Kappa B Inhibition Can Enhance Apoptosis of Differentiated Thyroid Cancer Cells Induced by 131I

Objective: To evaluate changes of nuclear factor-kappa B (NF-kB) during radioiodine 131 ( 131 I) therapy and whether NF-kB inhibition could enhance 131 I-induced apoptosis in differentiated thyroid cancer (DTC) cells in a synergistic manner. Methods: Three human DTC cell lines were used. NF-kB inhibition was achieved by using a NF-kB inhibitor (Bay 11-7082) or by p65 siRNA transfection. Methyl-thiazolyl-tetrazolium assay was performed for cell viability assessment. DNA-binding assay, luciferase reporter assay, and Western blot were adopted to determine function and expression changes of NF-kB. Then NF-kB regulated anti-apoptotic factors XIAP, cIAP1, and Bcl-xL were measured. Apoptosis was analyzed by Western blot for caspase 3 and PARP, and by flow cytometry as well. An iodide uptake assay was performed to determine whether NF-kB inhibition could influence radioactive iodide uptake. Results: The methyl-thiazolyl-tetrazolium assay showed significant decrease of viable cells by combination therapy than by mono-therapies. The DNA-binding assay and luciferase reporter assay showed enhanced NF-kB function and reporter gene activities due to 131 I, yet significant suppression was achieved by NF-kB inhibition. Western blot proved 131 I could increase nuclear NF-kB concentration, while NF-kB inhibition reduced NF-kB concentration. Western blot also demonstrated significant up-regulation of XIAP, cIAP1, and Bcl-xL after 131 I therapy. And inhibition of NF-kB could significantly downregulate these factors. Finally, synergism induced by combined therapy was displayed by significant enhancements o

Inhibitor of the transcription factor NF-κB, DHMEQ, enhances the effect of paclitaxel on cells of anaplastic thyroid carcinoma in vitro and in vivo

Anticancer drug paclitaxel (Ptx) effect on biochemical mechanisms, regulating apoptosis in anaplastic thyroid carcinoma cells, was studied. It was shown that in addition to apoptotic cell death, Ptx induces signa­ling cascades that ensure cell survival. Paclitaxel-induced activation of nuclear factor kappa B (NF‑κВ) leads to an increase of some antiapoptotic proteins expression such as survivin, cIAP, XIAP. A novel NF‑κВ inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), was found to enhance cytotoxic effect of Ptx in anaplastic thyroid carcinoma cells. An enhancement of caspase-3 and -9 activation and PARP cleavage as well as the decreased levels of proteins-inhibitors of apoptosis were observed when cells were treated with a combination of both drugs. Mitochondria transmembrane potential (ΔΨm) loss was observed at higher concentrations of Ptx and DHMEQ. NF-κВ inhibition also potentiates paclitaxel effect at tumors formed by xenotransplantation of FRO cells into mice. Tumor mass reduction, significantly different from the effects of each of the compounds alone, was observed in animals, treated with paclitaxel and NF-κВ inhibitor. Thus, the combined use of paclitaxel and NF-κВ inhibitor inhibits biochemical processes that contribute to the resistance of anaplastic thyroid carcinoma cells to paclitaxel action

Inhibition of the Wnt/β-catenin pathway enhances anti-tumor immunity in ovarian cancer

Background: The Wnt/β-catenin pathway is linked to tumorigenesis in a variety of tumors and promotes T cell exclusion and resistance to checkpoint inhibitors. We sought to determine whether a small molecule inhibitor of this pathway, WNT974, would impair tumor growth, affect gene expression patterns, and improve the immune response in human and murine ovarian cancer models. Methods: Human ovarian cancer cells were treated with WNT974 in vitro. RNAseq libraries were constructed and differences in gene expression patterns between responders and nonresponders were compared to The Cancer Genome Atlas (TCGA). Mice with subcutaneous or intraperitoneal ID8 ovarian cancer tumors were treated with WNT974, paclitaxel, combination, or control. Tumor growth and survival were measured. Flow cytometry and β-TCR repertoire analysis were used to determine the immune response. Results: Gene expression profiling revealed distinct signatures in responders and nonresponders, which strongly correlated with T cell infiltration patterns in the TCGA analysis of ovarian cancer. WNT974 inhibited tumor growth, prevented ascites formation, and prolonged survival in mouse models. WNT974 increased the ratio of CD8+ T cells to T regulatory cells (Tregs) in tumors and enhanced the effector functions of infiltrating CD4+ and CD8+ T cells. Treatment also decreased the expression of inhibitory receptors on CD8+ T cells. Combining WNT974 with paclitaxel further reduced tumor growth, prolonged survival, and expanded the T cell repertoire. Conclusions: These findings suggest that inhibiting the Wnt/β-catenin pathway may have a potent immunomodulatory effect in the treatment of ovarian cancer, particularly when combined with paclitaxel