Anticancer imidazoacridinone C-1311 is effective in androgen-dependent and androgen-independent prostate cancer cells

The androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and metastasis. Thus, blocking AR activity and its downstream signaling constitutes a major strategy for PCa treatment. Here, we report on the potent anti-PCa activity of a small-molecule imidazoacridinone, C-1311. In AR-positive PCa cells, C-1311 was found to inhibit the transcriptional activity of AR, uncovering a novel mechanism that may be relevant for its anticancer effect. Mechanistically, C-1311 decreased the AR binding to the prostate-specific antigen (<i>PSA</i>) promoter, reduced the PSA protein level, and, as shown by transcriptome sequencing, downregulated numerous AR target genes. Importantly, AR-negative PCa cells were also sensitive to C-1311, suggesting a promising efficacy in the androgen-independent PCa sub-type. Irrespective of AR status, C-1311 induced DNA damage, arrested cell cycle progression, and induced apoptosis. RNA sequencing indicated significant differences in the transcriptional response to C-1311 between the PCa cells. Gene ontology analysis showed that in AR-dependent PCa cells, C-1311 mainly affected the DNA damage response pathways. In contrast, in AR-independent PCa cells, C-1311 targeted the cellular metabolism and inhibited the genes regulating glycolysis and gluconeogenesis. Together, these results indicate that C-1311 warrants further development for the treatment of PCa

Soluble L-selectin levels in type I diabetes mellitus: a surrogate marker for disease activity?

L-selectin (CD62L) is a cell adhesion molecule which plays a key role in the initiation of leucocyte migration from blood vessels to sites of local inflammation. The aim of this study was to investigate T-lymphocyte expression of CD62L antigen and serum levels of soluble L-selectin (sL-selectin) in subjects with clinical and preclinical type I diabetes to determine whether they could provide surrogate markers for disease activity. CD62L selectin expression on memory T lymphocytes was studied by cytometric analysis in 22 patients with newly diagnosed type I diabetes, 20 first-degree relatives of patients with type I diabetes, 14 patients with Graves’ disease, and 22 healthy controls. sL-selectin levels were measured by enzyme-linked immunosorbent assay (ELISA) in enlarged groups of subjects in these categories, as well as in patients with long-standing type I diabetes, treated Graves’ disease and type II (non-insulin dependent) diabetes. L-selectin levels were also related to islet autoantibodies, human leucocyte antigen (HLA) genotype and L-selectin T668C gene polymorphisms. L-selectin expression on memory T lymphocytes was reduced in newly diagnosed diabetes and islet autoantibody positive siblings compared with controls. sL-selectin levels were significantly raised in newly diagnosed type I diabetes compared with controls, with intermediate levels in family members, both with and without islet autoantibodies, and in long-standing type I diabetes. Levels were also raised in patients with untreated Graves’ disease. Patients with type II diabetes had sL-selectin levels which did not differ from controls. sL-selectin levels correlated with the presence of diabetes-associated HLA alleles in both family members and controls; levels also fell with increasing age in family members. Multiple regression analysis showed that HLA genotype and age were independent determinants of sL-selectin levels. sL-selectin levels are raised at the time of diagnosis of type I diabetes and Graves’ disease and appear to be modulated by disease activity, but levels are determined predominantly by HLA-associated genetic susceptibility and age. sL-selectin may provide a late marker of autoimmune destruction of islets and sequential measurement may be useful in monitoring disease activity and the effect of interventions preceding type I diabetes

Expression pattern of heat shock proteins during acute thermal stress in the Antarctic sea urchin, Sterechinus neumayeri

© 2016 González et al. Background: Antarctic marine organisms have evolved a variety of physiological, life-history and molecular adaptations that allow them to cope with the extreme conditions in one of the coldest and most temperaturestable marine environments on Earth. The increase in temperature of the Southern Ocean, product of climate change, represents a great challenge for the survival of these organisms. It has been documented that some Antarctic marine invertebrates are not capable of generating a thermal stress response by means of an increase in the synthesis of heat shock proteins, which could be related with their low capacity for acclimatization. In order to understand the role of heat shock proteins as a compensatory response in Antarctic marine species to projected scenarios of increased seawater temperatures, we assessed the expression of the genes Hsp90, Grp78, Hyou1 and Hsc70 in the Antarctic sea urchin Sterechinus neumayeri under three thermal treatments (1 °C, 3 °C and 5 °C), for a period of exposure of 1, 24 and 48 h. Results: The results obtained showed that these genes were expressed themselves in all of the tissues analyzed in a constitutive form. During acute thermal stress, an overexpression of the Hsp90, Grp78 and Hyou1 genes was observed in coelomocyte samples at 3 °C after 48 h, while in esophageal samples, an increase in Hsp90 and Grp78 expression was observed after 48 h. Thermal stress at 5 °C, in general, did not produce a significant increase in the expression of the genes that were studied. The expression of Hsp70 did not show modifications in its expression as a result of thermal stress. Conclusions: S. neumayeri is capable of overe xpressing stress proteins as a result of thermal stress, however, this response is delayed and to a lesser degree compared to other Antarctic or temperate species. These results indicate that adult individuals could cope with the expected impacts caused by an increase in coastal sea temperatures in the Southern Ocean.Link_to_subscribed_fulltex