Inhibition of PCAF by Anacardic Acid Derivative Leads to Apoptosis and Breaks Resistance to DNA Damage in BCR-ABL-expressing Cells

Acetylation of histones and nonhistone proteins is a posttranslational modification which plays a major role in the regulation of intracellular processes involved in tumorigenesis. It was shown that different acetylation of proteins correlates with development of leukemia. It is proposed that histone acetyltransferases (HATs) are important novel drug targets for leukemia treatment, however data are still not consistent. Our previous data showed that a derivative of anacardic acid - small molecule MG153, which has been designed and synthesized to optimize the HAT inhibitory potency of anacardic acid, is a potent inhibitor of p300/CBP associated factor (PCAF) acetyltransferase. Here we ask whether inhibition of PCAF acetyltransferase with MG153 will show proapoptotic effects in cells expressing BCR-ABL, which show increased PCAF expression and are resistant to apoptosis. We found that inhibition of PCAF decreases proliferation and induces apoptosis, which correlates with loss of the mitochondrial membrane potential and DNA fragmentation. Importantly, cells expressing BCR-ABL are more sensitive to PCAF inhibition compared to parental cells without BCR-ABL. Moreover, inhibition of PCAF in BCR-ABL-expressing cells breaks their resistance to DNA damage-induced cell death. These findings provide direct evidence that targeting the PCAF alone or in combination with DNA-damaging drugs shows cytotoxic effects and should be considered as a prospective therapeutic strategy in chronic myeloid leukemia cells. Moreover, we propose that anacardic acid derivative MG153 is a valuable agent and further studies validating its therapeutic relevance should be performed

Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165

Inhibiting the interaction of neuropilin-1 (NRP-1) with vascular endothelial growth factor (VEGF) has become an interesting mechanism for potential anticancer therapies. In our previous works, we have obtained several submicromolar inhibitors of this interaction, including branched pentapeptides of general structure Lys(Har)-Xxx-Xxx-Arg. With the intent to improve the proteolytic stability of our inhibitors, we turned our attention to 1,4-disubstituted 1,2,3-triazoles as peptide bond isosteres. In the present contribution, we report the synthesis of 23 novel triazolopeptides along with their inhibitory activity. The compounds were synthesized using typical peptide chemistry methods, but with a conversion of amine into azide completely on solid support. The inhibitory activity of the synthesized derivatives spans from 9.2% to 58.1% at 10 μM concentration (the best compound Lys(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg, 3, IC50 = 8.39 μM). Synthesized peptidotriazoles were tested for stability in human plasma and showed remarkable resistance toward proteolysis, with half-life times far exceeding 48 h. In vitro cell survival test resulted in no significant impact on bone marrow derived murine cells 32D viability. By means of molecular dynamics, we were able to propose a binding mode for compound 3 and discuss the observed structure−activity relationships

The role of nibrin in Doxorubicin-induced apoptosis and cell senescence in nijmegen breakage syndrome patients lymphocytes

Nibrin plays an important role in the DNA damage response (DDR) and DNA repair. DDR is a crucial signaling pathway in apoptosis and senescence. To verify whether truncated nibrin (p70), causing Nijmegen Breakage Syndrome (NBS), is involved in DDR and cell fate upon DNA damage, we used two (S4 and S3R) spontaneously immortalized T cell lines from NBS patients, with the founding mutation and a control cell line (L5). S4 and S3R cells have the same level of p70 nibrin, however p70 from S4 cells was able to form more complexes with ATM and BRCA1. Doxorubicin-induced DDR followed by cell senescence could only be observed in L5 and S4 cells, but not in the S3R ones. Furthermore the S3R cells only underwent cell death, but not senescence after doxorubicin treatment. In contrary to doxorubicin treatment, cells from all three cell lines were able to activate the DDR pathway after being exposed to γ-radiation. Downregulation of nibrin in normal human vascular smooth muscle cells (VSMCs) did not prevent the activation of DDR and induction of senescence. Our results indicate that a substantially reduced level of nibrin or its truncated p70 form is sufficient to induce DNA-damage dependent senescence in VSMCs and S4 cells, respectively. In doxorubicin-treated S3R cells DDR activation was severely impaired, thus preventing the induction of senescence

Immunopositive tubules in sample 2–1.

<p><b>A.</b> Under low power magnification of section 05, several clusters of two or more tubules with strong MAGEA4 staining are visible. <b>B.</b> Higher power magnification of the boxed region in <b>A.</b> Five tubules with stronger MAGEA4 staining (*) are distinguishable from their neighbouring tubules with normal levels of MAGEA4 staining. In normal tubules, MAGEA4 stains the nucleus and cytoplasm of the spermatogonia on the basal lamina. In the immunopositive tubules additional MAGEA4-positive cells are present, forming a double row. <b>C.</b> Serial sections spanning 115 µm display consistently stronger staining for MAGEA4, FGFR3 and pAKT. Clusters of MAGEA4 positive cells are present in the lumen of this immunopositive tubule. No differences in staining for OCT2, Ki67, SAGE1 or SSX are observed. H&E staining (section 02) shows that the tubule in the centre contains few spermatocytes and no spermatids, whereas the tubule on the right hand side contains both spermatocytes and spermatids. A higher resolution image of the H&E staining is shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042382#pone.0042382.s004" target="_blank">Figure S4A</a>. Scale bar: 100 µm.</p