Rotenone Inhibits Autophagic Flux Prior to Inducing Cell Death

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HDAC inhibitors and decitabine are highly synergistic and associated with unique gene-expression and epigenetic profiles in models of DLBCL

Interactions between histone deacetylase inhibitors (HDACIs) and decitabine were investigated in models of diffuse large B-cell lymphoma (DLBCL). A number of cell lines representing both germinal center B-like and activated B-cell like DLBCL, patient-derived tumor cells and a murine xenograft model were used to study the effects of HDACIs and decitabine in this system. All explored HDACIs in combination with decitabine produced a synergistic effect in growth inhibition and induction of apoptosis in DLBCL cells. This effect was time dependent, mediated via caspase-3 activation, and resulted in increased levels of acetylated histones. Synergy in inducing apoptosis was confirmed in patient-derived primary tumor cells treated with panobinostat and decitabine. Xenografting experiments confirmed the in vitro activity and tolerability of the combination. We analyzed the molecular basis for this synergistic effect by evaluating gene-expression and methylation patterns using microarrays, with validation by bisulfite sequencing. These analyses revealed differentially expressed genes and networks identified by each of the single treatment conditions and by the combination therapy to be unique with few overlapping genes. Among the genes uniquely altered by the combination of panobinostat and decitabine were VHL, TCEB1, WT1, and DIRAS3.     

Effect of ESR1 and ESR2 gene polymorphisms on rheumatoid arthritis treatment with methotrexate

Rheumatoid arthritis (RA) is a complex autoimmune disease with clinical prevalence in women. Moreover, women have poorer response to treatment than men. Possible reasons for gender differences in response to treatment could be explained on the basis of sex hormones and their receptors. The optimal strategy in treatment of RA is to use effective disease modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX). The aim of the present study was to examine the association between polymorphisms in the ESR1 and ESR2 genes and the response to treatment of RA patients with methotrexate. The study was carried out on 156 women diagnosed with active rheumatoid arthritis, treated with MTX. Good responders were defined as patients who were receiving MTX and had a DAS28 of ≤ 2.4 after 6 months of therapy (patients with remission of disease symptoms). Poor-responders were defined as patients who were receiving MTX and had a DAS28 of > 2.4. There were no statistically significant associations of ESR1 and ESR2 gene polymorphisms with response to treatment. The results of the present study suggest that the polymorphisms rs9340799:A>G and rs2234693:T>C in ESR1 gene and rs4986938:G>A and 1256049:G>A in ESR2 gene are not associated with response to RA treatment with MTX.     

Expression of p21WAF1 in Astler-Coller stage B2 colorectal cancer is associated with survival benefit from 5FU-based adjuvant chemotherapy

In several, but not all, previous studies, positive p21^WAF1 expression has been suggested as an indicator of a good prognosis in patients with stage III/IV colorectal cancer. However, it is not known whether the same is true for stage B2 patients. The purpose of this study is to assess the influence of p21^WAF1 expression in tumor cells on disease-free survival (DFS) and overall survival (OS) of Astler–Coller stage B2 and C patients with colorectal cancer who underwent 5-fluorouracil-based adjuvant chemotherapy. Nuclear p21^WAF1 was detected by immunohistochemistry in tissue microarrays from 275 colorectal cancers. The expression of p21^WAF1 was associated with DFS (p = 0.025) and OS (p = 0.008) in the subgroup of stage B2 patients that was treated with adjuvant chemotherapy. In multivariate analysis, it remained the only independent prognostic parameter in relation to DFS and OS (p = 0.035 and p = 0.02, respectively). In the subgroup of 72 stage B2 patients with positive p21^WAF1 expression but not in the subgroup of 61 stage B2 patients with negative p21^WAF1 expression, adjuvant chemotherapy was associated with better DFS (85% 5-year survival versus 65% without chemotherapy, p = 0.03) and OS (96% versus 82%, p = 0.014). In the combined stage B2 and C group of patients treated with adjuvant chemotherapy, positive p21^WAF1 expression was also associated with better DFS and OS (p = 0.03, p = 0.002, respectively). Expression of p21^WAF1 in colorectal tumor cells identifies a subgroup of Astler–Coller stage B2 patients who could benefit significantly from 5FU-based chemotherapy and may improve the selection of patients for adjuvant chemotherapy.