D did, related. Moreover, it is important that chronic treatment of PC3 cells observed with 1 M not UNBS5162 either cell death by apoptosis or autophagy processes. Summarized in 10 m Ver significant Changed UNBS5162 PC 3 the growth of tumor cells kinetics, without egfr review a senescence, the inverse compared to DU-145 cells is observed. This difference can from their respective p53 status and / or the Ausma the result of p16 expression, which is a positive regulator of tumor suppressor pRb and in his own right, as reported by Campisi. A 1 M, UNBS5162 induces no such antitumor effects. Thus k can In vitro data obtained when the cells were of prostate cancer once with 1 or 10 M UNBS5162 not treated Ren explained, The activity t in vivo with a dose of 10 mg / kg iv UNBS5162 scheme that is likely be brought obtained with increased Hten plasma UNBS5162 well below 1 M of the time after administration in combination.
In contrast, GDC-0449 chronic treatment with 5 m 1 × UNBS5162 vitro to bring in good agreement with in vivo data. The presence or absence of active metabolites UNBS5162 must be taken best in vivo, And to this end an investigation into the compound, the metabolism is still see Genome-wide analysis to better characterize UNBS5162, mechanism of action first series of experiments were performed in vitro using of human cancer cells treated with PC UNBS5162 3 times over 24 hours, either 1 or 10 M, the results shown in Table 5A. A second series of experiments were then performed, which analyze the impact of chronic diseases in the in vitro treatment with 1 M UNBS5162, the results were shown in Table 5B.
The in vitro treatment of PC3 cells with a single dose of 10 M UNBS5162 materially impair Changed nuclear organization and biogenesis of these cells by increasing Increase significantly the H Height of expression, at least at the mRNA level, different types of histones . Narita et al. described a distinct heterochromatic structure that accumulates in senescent human fibroblasts, they have called senescence associated heterochromatic foci. CO formation SAHF F filled With the recruitment of heterochromatin proteins And the retinoblastoma tumor suppressor E2F-responsive promoters and repression of E2F target genes with stably connected. Remarkably, h Depends both SAHF formation and silencing of E2F target genes on the integrity of t of the Rb pathway and do not occur in cells of F Reversibly arrested.
SAHF with macro H2A, a histone H2A variant silence transcription, a characteristic of heterochromatin ugetieren enriched in S. UNBS5162 obtains at least 10 million Ht fa It marked the H Height of heterochromatin in PC cells through a 3-erh Increase the number of histones, at least at the mRNA level. However UNBS5162 decreased 2.6 times the level of mRNA expression, the H2AFY produces macroH2A1.2. As mentioned Above, an in vitro data obtained when the cells were of prostate cancer treated once with 10 M UNBS5162 k can The apparent activity of t in vivo explained Ren, but no further investigation of the compound of the effects on chromatin remodeling was performed. The note has been affected several other groups of genes also Table 4. Abstract of 10 M UNBS5162 in vitro effects on proliferation and apoptosis. PC 3 of 145 growth arrest quantitative videomicroscopy G2 phase blockade pRb expression of E2F1 senescence � term The apoptotic cell death � Utophag � �A
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