Abstract Background: Despite advances in chemotherapeutic treatment of acute lymphoblastic leukemia (ALL), drug resistance in ALL remains a major problem warranting new treatment strategies. Recent studies have demonstrated that survivin, a member of the inhibitor of apoptosis (IAP) family proteins, is upregulated in ALL of relapsed patients but not in drug-sensitive ALL. The expression of survivin depends on the formation of a complex between catenin (beta or gamma) and its co-activator CBP. T-cell factor (TCF)/catenin/CBP mediated transcription is involved in self-renewal of progenitor cells. However, a switch to TCF/catenin/p300 mediated transcription, which can be induced pharmacologically with ICG-001, a novel specific inhibitor of binding to the N-terminus of CBP, is described as critical to inhibit CBP-mediated self-renewal. We hypothesized that selective suppression of CBP/catenin signaling using ICG-001 offers a promising therapeutic principle to eradicate drug resistant ALL and showed previously that ICG-001 can sensitize patient-derived (primary) pre-B ALL cells to chemotherapy in vitro and in vivo. However, the underlying mechanism has not been described. Results: For this purpose, we initially determined expression of nuclear and cytosolic β- and γ-catenin expression in 13 primary ALL cases encompassing various cytogenetic aberrations by Western blot. Primary pre-B ALL cells were treated with and without ICG-001 and co-cultured with a murine stromal layer (OP9 cells) for 48 hours. Co-Immunoprecipitation showed that the binding of β- and γ-catenin with CBP, but not with p300, was inhibited by ICG-001 indicating that ICG-001 binds CBP and selectively disrupts β- and γ-catenin/CBP interaction. To determine the effect of ICG-001 on self-renewal in ALL, we performed a colony forming (CFU) assay with two primary ALL cells (LAX7R, SFO2) treated with single agent ICG-001 (10 m and 25 m). LAX7R showed a significant reduction with ICG-001 treatment (10 m and 25 m) compared with media only group (331.3× 42.8 and 57×13.5 vs 698.3× 68.4; p<0.05) in primary platings, and there were no colonies found in secondary platings of cells treated with ICG-001 (25 m), indicating that ICG-001 abrogates self-renewal of ALL cells. Similarly SFO2 cells showed no secondary colony counts with ICG-001 treatment (25 m) whereas control cells were replatable. These experiments were repeated three times in triplicate. Preclinical in vitro evaluation of five primary ALL cells treated continuously with ICG-001 (10μM- or, 25μM) or DMSO as vehicle control with and without chemotherapy consisting of Nilotinib for Philadelphia chromosome (Ph) positive ALL and Vincristine, Dexamethasone and L-Asparaginase for Ph negative ALL, that chemotherapy alone cannot eradicate primary ALL cells. However, in combination with ICG-001, chemotherapy led to the eradication of all five primary ALL cases, indicating that CBP/catenin antagonism can overcome drug resistance in ALL. Conclusion: Taken together, our data shows that targeting CBP/β- and γ-catenin by the small molecule inhibitor ICG-001 can abrogate primary ALL by inhibition of self-renewal of ALL cells. These findings provide the basis for a new treatment approach against drug resistant ALL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B218.
Abstract Combretastatin A‐4 (CA4), a tubulin inhibitor, binds to the colchicine site of tubulin, inhibits tubulin polymerization, and leads to the apoptosis of tumor cells. However, the poor hydrophilicity and blood–brain barrier (BBB) penetration ability of CA4 hampers its application in the treatment of glioma. In this study, a novel combretastatin A‐4 derivative (CA4D) was designed and developed, which was further conjugated with glucose via disulfide‐bond‐bridged (CA4D‐SS‐Glu) to enhance the BBB penetration capacity. The obtained CA4D‐SS‐Glu conjugate displayed a suitable water partition coefficient and the superior ability across BBB in vitro and in vivo. In addition, the CA4D‐SS‐Glu exhibited rapid redox‐responsive drug release in the presence of glutathione, enhanced in vitro cytotoxicity, and cell apoptosis. Our data further confirmed that CA4D‐SS‐Glu inhibited proliferation, and restrained migration via affecting microtubule stabilization. Additionally, the conjugate also showed the highest antiproliferative and antitumor action on glioma in vivo as compared to CA4D and CA4. Taken together, the novel CA4D‐SS‐Glu conjugate possess improved physicochemical property and BBB penetration ability, reduction triggered release of CA4D, and efficient antiproliferative activity. These results provided a novel and effective entry to the treatment of glioma.
-The ternary system of yBiGaO 3 -(1-x-y) BiScO 3 -xPbTiO 3 (BGS-PT) ceramics was prepared by using conventional mixing oxide process. X-ray diffraction analysis reveals that BGS-PT ceramics show the perovskite structure. The Curie temperature of BGS-PT ceramics was found to be increased with increasing of BiGaO 3 content. However, more BiGaO 3 content would lead to sharply decreased piezoelectric properties of BGS-PT ceramics and the secondary phase would be formed in BGS-PT system. BGS-PT ceramics with x, y=0.56, 0.19 shows a high Curie temperature T c and large piezoelectric constant d 33 of 501degC and 152 pC/N, respectively. The high-T c of BGS-PT ceramics with the useable piezoelectric properties suggested those future high-temperature applications.
The molybdenum alloy sheets composite strengthened by silicon and lanthanum oxide were prepared by powder metallurgy technology with Mo-La2O3(0.3wt%) and Si(0, 0.1, 0.3wt%) powders and thermo-mechanically processing. The influences of silicon content on the microstructure and mechanical properties of the final molybdenum alloy sheets were tested and analysized. The results show that the addition of lanthanum oxide and silicon can refine the alloys grain size. The introduction of lanthanum oxide particles can increase the yield strength. Although the molybdenum alloys with 0.3wt% silicon have solid solution strengthening effect, the alloys with 0.1 wt% silicon exhibits obvious solid solution softening effect at room temperature. The strengthening mechanisms are quantitatively assessed, which well explain the increase or decrease in yield strength with respect to grain size, lanthanum oxide particle and silicon solid solution.
Two series of novel fraxinellone-based thioethers containing 1,3,4-oxadiazole moiety were prepared as insecticidal agents against the oriental armyworm, Mythimna separata Walker. The structural assignment was based on the spectroscopic and X-ray analysis data. Among all the target compounds, compounds 4b , 4k , 5b , 5j and 5k exhibited more potent insecticidal activity with final mortality rates (FMRs) of more than 65%, especially 4k with the FMR of 75.9%, when compared with toosendanin. Some interesting results of structure–activity relationships are also discussed.
Abstract As global aging accelerates, the prevention and treatment of age-related bone diseases are becoming a critical issue. In the process of senescence, bone marrow mesenchymal stem cells (BMSCs) gradually lose the capability of self-renewal and functional differentiation, resulting in impairment of bone tissue regeneration and disorder of bone tissue homeostasis. Alteration in epigenetic modification is an essential factor of BMSC dysfunction during aging. Its transferability and reversibility provide the possibility to combat BMSC aging by reversing age-related modifications. Emerging evidence demonstrates that epigenetic therapy based on aberrant epigenetic modifications could alleviate the senescence and dysfunction of stem cells. This review summarizes potential therapeutic targets for BMSC aging, introduces some potential approaches to alleviating BMSC aging, and analyzes its prospect in the clinical application of age-related bone diseases.
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