Clinical trials for multiple myeloma and lymphomas.

<p>Clinical trials for multiple myeloma and lymphomas.</p

Chromatin structure determines gene expression and hallmarks of cancer.

<p>(A) Chromatin can assume active and repressive states. Repressive states are supercoiled and enriched for DNA and histone methylation marks; active states are accessible to transcription factors (TFs) and enriched for histone marks (such as H3K27ac and H3K4me3). Restrictive chromatin raises epigenetic barriers and blocks cell state transition, while permissive chromatin reduces epigenetic barriers and determines alternate cell states. (B) Aberrant permissive and restrictive chromatin states cause cancerogenesis and give rise to hallmarks of cancer.</p

Clinical trials for breast cancer.

<p>Clinical trials for breast cancer.</p

The microRNAs associated with molecular subtypes of BC.

<p>The microRNAs associated with molecular subtypes of BC.</p

Integrated genome-wide analysis.

<p>Integrating and combining data from different platforms (genome-DNA sequence, transcriptome, proteome, metabolome, and epigenome) leads to a better understanding of the basis of cancer and paves the way toward personalized medicine.</p

Image_1_Forskolin Sensitizes Human Acute Myeloid Leukemia Cells to H3K27me2/3 Demethylases GSKJ4 Inhibitor via Protein Kinase A.TIF

<p>Acute myeloid leukemia (AML) is an aggressive hematological malignancy occurring very often in older adults, with poor prognosis depending on both rapid disease progression and drug resistance occurrence. Therefore, new therapeutic approaches are demanded. Epigenetic marks play a relevant role in AML. GSKJ4 is a novel inhibitor of the histone demethylases JMJD3 and UTX. To note GSKJ4 has been recently shown to act as a potent small molecule inhibitor of the proliferation in many cancer cell types. On the other hand, forskolin, a natural cAMP raising compound, used for a long time in traditional medicine and considered safe also in recent studies, is emerging as a very interesting molecule for possible use in cancer therapy. Here, we investigate the effects of forskolin on the sensitivity of human leukemia U937 cells to GSKJ4 through flow cytometry-based assays (cell-cycle progression and cell death), cell number counting, and immunoblotting experiments. We provide evidence that forskolin markedly potentiates GSKJ4-induced antiproliferative effects by apoptotic cell death induction, accompanied by a dramatic BCL2 protein down-regulation as well as caspase 3 activation and PARP protein cleavage. Comparable effects are observed with the phosphodiesterase inhibitor IBMX and 8-Br-cAMP analogous, but not by using 8-pCPT-2′-O-Me-cAMP Epac activator. Moreover, the forskolin-induced enhancement of sensitivity to GSKJ4 is counteracted by pre-treatment with Protein Kinase A (PKA) inhibitors. Altogether, our data strongly suggest that forskolin sensitizes U937 cells to GSKJ4 inhibitor via a cAMP/PKA-mediated mechanism. Our findings provide initial evidence of anticancer activity induced by forskolin/GSKJ4 combination in leukemia cells and underline the potential for use of forskolin and GSKJ4 in the development of innovative and effective therapeutic approaches for AML treatment.</p

ARHGEF3 controls HDACi-induced differentiation via RhoA-dependent pathways in acute myeloid leukemias

<div><p>Altered expression and activity of histone deacetylases (HDACs) have been correlated with tumorigenesis. Inhibitors of HDACs (HDACi) induce acetylation of histone and non-histone proteins affecting gene expression, cell cycle progression, cell migration, terminal differentiation and cell death. Here, we analyzed the regulation of ARHGEF3, a RhoA-specific guanine nucleotide exchange factor, by the HDACi MS275 (entinostat). MS275 is a well-known benzamide-based HDACi, which induces differentiation of the monoblastic-like human histiocytic lymphoma cell line U937 to monocytes/macrophages. Incubation of U937 cells with MS275 resulted in an up regulation of ARHGEF3, followed by a significant enhancement of the marker of macrophage differentiation CD68. ARHGEF3 protein is primarily nuclear, but MS275 treatment rapidly induced its translocation into the cytoplasm. ARHGEF3 cytoplasmic localization is associated with activation of the RhoA/Rho-associated Kinase (ROCK) pathway. In addition to cytoskeletal rearrangements orchestrated by RhoA, we showed that ARHGEF3/RhoA-dependent signals involve activation of SAPK/JNK and then Elk1 transcription factor. Importantly, MS275-induced CD68 expression was blocked by exposure of U937 cells to exoenzyme C3 transferase and Y27632, inhibitors of Rho and ROCK respectively. Moreover, ARHGEF3 silencing prevented RhoA activation leading to a reduction in SAPK/JNK phosphorylation, Elk1 activation and CD68 expression, suggesting a crucial role for ARHGEF3 in myeloid differentiation. Taken together, our results demonstrate that ARHGEF3 modulates acute myeloid leukemia differentiation through activation of RhoA and pathways directly controlled by small GTPase family proteins. The finding that GEF protein modulation by HDAC inhibition impacts on cell differentiation may be important for understanding the antitumor mechanism(s) by which HDACi treatment stimulates differentiation in cancer.</p></div

Molecular analysis of the effects of Piroxicam and Cisplatin on mesothelioma cells growth and viability-4

Nd/or CDDP for different times. Electrophoretic bands were analyzed using Scion Image program. Experiments were repeated in triplicate and media values and standard deviations were calculated. CTRL = control; P = piroxicam; C = CDDP.<p><b>Copyright information:</b></p><p>Taken from "Molecular analysis of the effects of Piroxicam and Cisplatin on mesothelioma cells growth and viability"</p><p>Journal of Translational Medicine 2008;6():27-27.</p><p>Published online 22 May 2008</p><p>PMCID:PMC2412853.</p><p></p

Molecular analysis of the effects of Piroxicam and Cisplatin on mesothelioma cells growth and viability-2

Hase distribution. All the experiments were performed at least 3 times. Media ± Standard deviation of experiments is expressed as percentage of total cells. CTRL = control; P = piroxicam; C = CDDP.<p><b>Copyright information:</b></p><p>Taken from "Molecular analysis of the effects of Piroxicam and Cisplatin on mesothelioma cells growth and viability"</p><p>Journal of Translational Medicine 2008;6():27-27.</p><p>Published online 22 May 2008</p><p>PMCID:PMC2412853.</p><p></p

Molecular analysis of the effects of Piroxicam and Cisplatin on mesothelioma cells growth and viability-1

-2 OS lysate as negative control. Normalization with actin level. The experiments were done in triplicate with comparable results.<p><b>Copyright information:</b></p><p>Taken from "Molecular analysis of the effects of Piroxicam and Cisplatin on mesothelioma cells growth and viability"</p><p>Journal of Translational Medicine 2008;6():27-27.</p><p>Published online 22 May 2008</p><p>PMCID:PMC2412853.</p><p></p