The remaining Mocetinostat in vitro mutations affect protein stability only slightly, suggesting that only a small subset of side chain interactions within the hPin1 WW domain are mandatory for acquiring and maintaining a stable, cooperatively folded beta-sheet structure.”
“Imatinib is a substrate
for hOCT1 (SLC22A1) and inhibitors of this influx transporter, such as amantadine and prazosin, have previously been shown to decrease cellular imatinib uptake. However, here we report that in longer term experiments, both drugs paradoxically increase the cytotoxicity of all three currently licensed tyrosine kinase inhibitors (TKIs), imatinib, nilotinib and dasatinib. This effect is due to release of intracellular calcium from the endoplasmic reticulum (ER), with changes in mitochondrial calcium and alterations in mitochondrial XL184 in vitro membrane permeability, resulting in caspase-mediated apoptosis. The effect is confined to BCR-ABL-positive cells, and is greater in primary cells than in cell lines. Furthermore, in primary cells at original diagnosis, the effect is only seen in samples from patients destined to become complete cytogenetic responders to imatinib. These results indicate that calcium
release from the ER, here induced by amantadine or prazosin, may prime BCR-ABL-positive cells to TKI-induced apoptosis. Amantadine/prazosin primed TKI cytotoxicity in vitro may be a useful test for the level of ER-releasable calcium, and may be of prognostic value. Leukemia (2012) 26, 490-498; doi:10.1038/leu.2011.231; published online 2 September 2011″
“In-111-DTPA-anti-gamma H2AX-Tat, which combines Idelalisib mouse an anti-gamma H2AX antibody with a cell-penetrating peptide, Tat, and the Auger electron-emitting radioisotope, In-111, targets the DNA damage signalling protein, gamma H2AX, and has potential as a probe for imaging DNA damage in vivo. The goal of this study was to investigate whether In-111-DTPA-anti-gamma H2AX-Tat labelled to high specific activity (6 MBq/mu g) can amplify treatment-related DNA damage for therapeutic gain.
Methods: MDA-MB-468 and MDA-MB-231/H2N (231-H2N)
breast cancer cells were incubated with In-111-DTPA-anti-gamma H2AX-Tat (3MBq, 6MBq/mu g) or a control radioimmunoconjugate, In-111-DTPA-mIgG-Tat, and exposed to IR or bleomycin. DNA damage was studied by counting gamma H2AX foci and by neutral comet assay. Cytotoxicity was evaluated using clonogenic assays. In-111-DTPA-anti-gamma H2AX-Tat was administered intravenously to 231-H2N-xenograft-bearing Balb/c nu/nu mice in tumor growth inhibition studies.
Results: The number of gamma H2AX foci was greater after exposure of cells to IR (10Gy) plus In-111-DTPA-anti-gamma H2AX-Tat compared to IR alone (20.6 +/- 2.5 versus 10.4 +/- 2.3 foci/cell; P<.001). In-111-DTPA-anti-gamma H2AX-Tat resulted in a reduced surviving fraction in cells co-treated with IR (4Gy) versus IR alone (5.2%+/- 0.