Mitoxantrone triggers immunogenic prostate cancer cell death via p53-dependent PERK expression.

BACKGROUND: Mitoxantrone (MTX) is a synthetic compound used as a second line chemotherapeutic drug for prostate cancer. It has been reported to trigger immunogenic cell death (ICD) in animal model studies, but the underlying mechanism is not fully understood yet, especially not in prostate cancer cells. METHODS: ICD was determined by assessing the release of damage-associated molecular patterns (DAMPs) in the prostate cancer-derived cell lines LNCaP, 22RV1 and PC-3. Short hairpin RNAs (shRNAs) were used to knock down target gene expression. Phagocytosis was assessed using a dual labeling technology in dendric cells co-cultured with cancer cells. The PERK gene promoter was cloned for dual luciferase assays. Chromatin immunoprecipitation (ChIP) was used to determine p53 protein-DNA binding activity. Immunocompetent mice and murine RM-1 prostate cancer cells were used for vaccination experiments. RESULTS: MTX treatment induced typical characteristics of DAMP release, including increased cell surface exposure of calreticulin (CALR), and extracellular release of ATP and high mobility group box-1 (HMGB1) protein. MTX also enhanced phagocytosis by dendritic cells. Moreover, MTX treatment increased eukaryotic initiation factor 2α (eIF2α) S51 phosphorylation, which was reduced when PERK and GCN2 were silenced using shRNAs. In addition, PERK or GCN2 silencing significantly reduced MTX-induced release of DAMPs in vitro and anti-tumor immunity in vivo. MTX treatment also resulted in dendritic cell activation in mice, which was attenuated when PERK or GCN2 were silenced in cancer cells used for vaccination. Further analysis revealed that PERK and GCN2 expression was enhanced by MTX treatment, of which PERK, but not GCN2, was enhanced via a p53-dependent mechanism. CONCLUSION: MTX triggers ICD by activating eIF2α via PERK/GCN2 upregulation in prostate cancer cells. MTX-induced PERK expression upregulation depends on the p53 pathway, while that of GCN2 requires further investigation.

Ion-Exchange Fabrication of Hierarchical Al-MOF-Based Resin Catalysts for the Tandem Reaction.

Metal-organic framework (MOF)-supported macroscale resin catalysts, IRA900(xOH)-MIL-101(Al)-NH2 (x means the concentration of NaOH), with spatially isolated antagonistic acid-base active sites were successfully synthesized through a novel strategy by ion exchange and in situ solvothermal methods. The hierarchical pore system of the as-prepared catalysts effectively promotes the mass transfer and contacts with catalytic active centers during the organic reactions. Therefore, the environmentally friendly catalysts exhibit excellent superior activity and stability in one-pot deacetalization-Knoevenagel condensation reaction, and the yield by optimal IRA900(0.2OH)-MIL-101(Al)-NH2 reaches close to 99% after 5 h at 110 °C. Thanks to the millimeter-sized resin carrier and robust sphere morphology, the recycling of the as-prepared catalysts only requires natural sedimentation. This work presents an effective strategy to build low-toxic acid-base catalysts by combining the advantages of ion-exchange resins and functionalized MOF materials.

Periodic Mesoporous Organosilicas as Efficient Nanoreactors in Cascade Reactions Preparing Cyclopropanic Derivatives.

In this work, three organosilica precursors functionalized with carbamate moieties were synthesized by condensing of 3-isocyanatopropyltriethoxysilane and coupling regents of either hydroquinone (HQ), bisphenol A (BPA), or 1,1'-bi-2-naphthol (BN). These organosilica precursors were covalently bonded in the framework of periodic mesoporous organosilicas by co-condensation and hydrolysis with tetraethyl orthosilicate (TEOS) under hydrothermal treatment. The compositions and physical properties were characterized with FTIR, XRD, thermogravimetric/differential thermal analysis (TG/DTA), 29 Si NMR, 13 C NMR spectroscopies, SEM, TEM, and BET technologies. These characterizations suggest that three different structures were formed as the result of different sizes and compositions of the organosilica precursors. The three mesoporous organosilicas were applied as heterogeneous catalysts in the one-pot cascade Knoevenagel and Michael cyclopropanic reactions for the synthesis of cyclopropanic derivatives and showed excellent activity and selectivity. The highest conversion was obtained with mesoporous catalyst (MC)-HQ owing to its ordered mesostructure, highest surface area, and weakest stereo effect of the organic linking groups compared with MC-BAP and MC-BN. This methodology employed cheaper and more easily obtainable raw materials as reagents over the traditional alkene additive system and these heterogeneous catalysts exhibit superior performance and recyclability than typical homogeneous organic catalysts.

Synthesis of Porous Fe3 C-Based Composite Beads as Heterogeneous Oxidation Catalysts.

A series of multiscale cementite/iron/porous carbon (CIPC-T) composites with extremely low nitrogen content and millimeter-size spherical morphology were prepared by simple carbothermal pyrolysis of resin spheres exchanged with ferric oxalate anions. CIPC-T materials are composed of highly disperse core-shell-structured Fe3 C/Fe@graphitic carbon (CI@GC) nanoparticles embedded in a porous amorphous carbon framework. A mechanism for the formation of the composites is proposed on the basis of the results of XRD, SEM, TEM, and thermogravimetric analysis. The Fe3 C content can be easily controlled just by using different carbothermal temperatures. The CIPC-T materials proved to be active as heterogeneous catalysts for oxidation of ethylbenzene to acetophenone and Fenton-like oxidation of methylene blue. For the first time, the role of Fe3 C in catalytic oxidation was confirmed. The spherical morphology of the composites and magnetic property facilitate separation of the catalyst from the reaction solution. More importantly, no leaching of iron active sites occurs during the reactions and the catalyst can be reused in continuous runs without obvious loss of activity. Such high stability of iron sites in the composites is ascribed to the protecting outer graphitic carbon shell of CI@GC.

Hybrid mesoporous organosilicas with molecularly imprinted cavities: towards extended exposure of active amino groups in the framework wall.

Hybrid molecularly imprinted mesoporous silicas were synthesized by co-condensation of tetraethoxysilane and functional organosilica precursors of HQP and BPAP, in which hydroquinone (HQ) and bisphenol A (BPA) were linked as imprinting molecules. Owing to the existence of a thermally reversible covalent bond of carbamate (-NH-COO-), the imprinting molecules could be eliminated under thermal treatment and molecularly imprinted cavities were formed in the framework wall. All of these materials were used to catalyze heterogeneous Knoevenagel reactions and proved to exhibit higher catalytic conversion and turnover frequency (TOF) number compared with the materials with imprinting molecules, which is attributed to the presence of amino groups with higher basicity and molecularly imprinted cavities. Importantly, compared with amino functionalized SBA-15 materials, the decisive role of molecularly imprinted cavities in the enhanced accessibility of amino groups in a mesoporous framework was further confirmed. Moreover, the size of imprinting molecules has an influence on the catalytic conversion and TOF values: imprinting molecules with relatively bulkier size tend to provide higher accessibility to the active sites. The amino groups in the framework are extremely stable during the reaction procedure and recycling process.