ABSTRACT
Derivatives of the Chinese traditional medicine indirubin have shown potential for the treatment of cancer through a range of mechanisms. This study investigates the impact of 6'-bromoindirubin-3'-acetoxime (BiA) on immunosuppressive mechanisms in glioblastoma (GBM) and evaluates the efficacy of a BiA nanoparticle formulation, PPRX-1701, in immunocompetent mouse GBM models. Transcriptomic studies reveal that BiA downregulates immune-related genes, including indoleamine 2,3-dioxygenase 1 (IDO1), a critical enzyme in the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) immunosuppressive pathway in tumor cells. BiA blocks interferon-γ (IFNγ)-induced IDO1 protein expression in vitro and enhances T cell-mediated tumor cell killing in GBM stem-like cell co-culture models. PPRX-1701 reaches intracranial murine GBM and significantly improves survival in immunocompetent GBM models in vivo. Our results indicate that BiA improves survival in murine GBM models via effects on important immunotherapeutic targets in GBM and that it can be delivered efficiently via PPRX-1701, a nanoparticle injectable formulation of BiA.
Subject(s)
Glioblastoma , Animals , Mice , Glioblastoma/drug therapy , Tryptophan/pharmacology , Kynurenine , Oximes/pharmacology , Oximes/therapeutic useABSTRACT
To obtain comprehensive information about the genes involved in BCR/ABL-dependent leukemogenesis, samples from 15 chronic myelogenous leukemia (CML) patients and seven normal donors were analysed using a cDNA microarray assay. After subtraction of the artificial, random or cross-hybridization signals, data about 5315 genes have been effectively analysed in all samples. The assay revealed >/=4-fold difference in the average expression of 263 genes in all CML samples when compared to normal counterparts, with 148 genes being upregulated and 115 being downregulated. Differentially expressed genes include those associated with BCR/ABL-induced abnormalities in signal transduction, gene transactivation, cell cycle, apoptosis, adhesion, DNA repair, differentiation, metabolism and malignant progression. Interestingly, CML-blast crisis cells in peripheral blood differ from those from bone marrow, indicating major changes in gene expression profiles upon entering into the bloodstream. Moreover, BCR/ABL modulates expression of genes, which are involved in regulation of chromosome/chromatin/DNA dynamics during S and M cell cycle phase. Moreover, the ability of CML cells to recognize and respond to a pathogen infection may be compromised. Altogether, this work provides a large body of information regarding gene expression profiles associated with CML and also represents a source of potential targets for CML therapeutics.