Benzothiazinone [KLH]

Administration of lipophilic drugs is often restricted by poor aqueous solubility (especially in blood), limited membrane permeability, uncontrolled drug leakage, and aggregation of lipophilic drugs. As a new nanocarrier concept, LC@ZrO(mdp)@ZrO(HPO4) core@shell nanocontainers (LC: lipophilic cavity; mdp: monododecylphosphate) are presented. As a proof of concept, the nanocontainers are used to encapsulate different types of lipophilic molecules such as the fluorescent dye lumogen red (LR), the cytostatic drug irinotecan (ITC), the insecticide cypermethrin (CM), and the tuberculosis antibiotic benzothiazinone-043 (BTZ). Synthesis strategy and material structure of the nanocontainers are discussed in detail. LR@ZrO(mdp)@ZrO(HPO4), as the first example, shows intense red emission and successful incorporation of LR into the nanocontainers. As ex vivo application, CM@ZrO(mdp)@ZrO(HPO4) nanocontainers can be used to repel and even kill mosquitoes or flies being in contact with the insecticide-loaded nanocontainers. The drugs ITC and BTZ-after encapsulation in ITC@ZrO(mdp)@ZrO(HPO4) and BTZ@ZrO(mdp)@ZrO(HPO4) nanocontainers-show high activity at low cytotoxicity in in vitro studies against tumor cells (HeLa, SK-Mel-28, HTC116, A549, RAW264.7) and tuberculosis (Mycobacterium tuberculosis-infected macrophages). Taken together, the different lipophilic molecules (LR, CM, ITC, BTZ) point to the adaptability and performance of the novel zirconyl hydrogenphosphate nanocontainer concept.

Bortezomib (BTZ), a well-established proteasome inhibitor used in the clinical therapy, leads the modulation of several biological alterations and in turn induces apoptosis. Although clinical trials with BTZ have shown promising results for some types of cancers, but not for some others, including those of the breast. The molecular basis of BTZ resistance in breast cancer remains elusive. In the present study, we found that cellular O-GlcNAc modification was dramatically elevated by BTZ treatment in intrinsic resistant MCF-7 and T47D cells, but not in sensitive MDA-MB-231 cells. A progressive increase in O-GlcNAcylation characterized the increased acquired resistance of MDA-MB-231-derived cells. We showed that elevated O-GlcNAc subsequently modified breast cancer related pioneer factor FOXA1 and reduced its protein stability. Further, we demonstrated that FOXA1 attenuation was involved in transcriptional downregulation of proapoptotic Bim and thus suppressed breast cancer cell apoptosis. Finally, the combination of O-GlcNAc inhibitor L01 to BTZ sensitized resistant cells. Our results have revealed a new regulatory mechanism that involves O-GlcNAc elevation mediated Bim deficiency, which plays a key role in the apoptotic dysregulation and BTZ resistance in breast cancer cells.