EZH2 is a critical epigenetic regulator that is deregulated in various types of cancers including multiple myeloma (MM). In the present study, we hypothesized that targeting EZH2 might induce apoptosis in myeloma cells including stem cell-like cells (CSCs). We investigated the effect of EZH2 inhibition on MM cells using a potent inhibitor (GSK126). The results showed that GSK126 effectively abrogated the methylated histone 3 (H3K27me3) level in MM.1S and LP1 cells, and inhibited the number of live cells and colony formation in soft agar of six MM cell lines. GSK126 induced massive apoptosis in MM.1S, LP1 and RPMI8226 cells. Progressive release of mitochondrial cytochrome c and AIF into the cytosol was detected in GSK126-treated MM cells. GSK126 treatment elicited caspase-3-dependent MCL-1 cleavage with accumulation of proapoptotic truncated MCL-1. These results suggested that GSK126 triggers the intrinsic mitochondrial apoptosis pathway. Enhanced apoptosis was observed in the combination of GSK126 with bortezomib. Using ALDH and side population (SP) assays to characterize CSCs, we found that GSK126 eliminated the stem-like myeloma cells by blocking the Wnt/β-catenin pathway. The in vivo anti-tumor effect of GSK126 was confirmed by using RPMI8226 cells in a xenograft mouse model. In conclusion, our findings suggest that EZH2 inactivation by GSK126 is effective in killing MM cells and CSCs as a single agent or in combination with bortezomib. Clinical trial of GSK126 in patients with MM may be warranted.
Selenium nanoparticles (SeNPs) are recently emerging as promising anticancer agents because of their high bioavailability, low toxicity and remarkable anticancer activities. However, the effects of surface physicochemical properties on the biological actions remain elusive. Herein we decorated SeNPs with various water-soluble polysaccharides extracted from various mushrooms, to compare physical characteristics and anticancer profile of these SeNPs. The results showed that the prepared spherical SeNPs displayed particle sizes at 91−102 nm, and kept stable in aqueous solution for up to 13 weeks. However, different decoration altered the tumor selectivity of the SeNPs, while gastric adenocarcinoma AGS cells showed relative highest sensitivity. Moreover, PTR-SeNPs demonstrated potent in vivo antitumor, by inducing caspases-and mitochondria-mediated apoptosis, but showed no obvious toxicity to nomal organs. Taken together, this study offers insights into how surface decoration can tune the cancer selectivity of SeNPs and provides a basis for engineering particles with increased anticancer efficacy.
This is the first paper to identify a subgroup of non-Caucasian patients with low dispositional optimism who may be at risk for developing regret after microsurgical breast reconstruction. Possible strategies to ameliorate regret may involve addressing cultural and language barriers, setting realistic expectations, and providing more support during the pre-operative decision-making phase.
Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovery of targeted therapies for personalized cancer medicine. Herein, cancer targeting RGD peptide has been covalently conjugated to selenadiazole derivative (RGD-SeD) to improve its cancer selectivity. The RGD decoration significantly enhances the anticancer efficacy of RGD-SeD in αVβ3 integrin-overexpressing HepG2 liver cancer cells but not in normal liver cells. Cellular uptake assay and fluorescent imaging confirmed the selectivity of RGD-SeD to integrin-overexpressing cancer cells. RGD-SeD strongly sensitizes HepG2 cells to clinically used X-ray radiotherapy through ROS overproduction, which triggers DNA damage-mediated apoptosis and G2/M cell cycle arrest. This X-ray-responsive DNA damage activates p53 signaling pathways by phosphorylation of ATM/ATR and γ-H2A.X. Furthermore, in a HepG2 nude mice xenograft model, the combined treatment of RGD-SeD and X-ray demonstrates potent in vivo antitumor efficacy via induction of apoptotic cell death but shows no toxicity on the functions of major organs. In summary, this study provides a strategy to design a selenium-based cancer targeting radiosensitizer for precise cancer therapy.
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