Molecular Aspects of Breast Cancer Metastasis to the Brain

Our knowledge of the biology underlying the development of brain metastases (BM) from breast cancer has improved over the last decade due to large clinical epidemiological studies, animal models of metastasis, and the use of high-resolution gene expression profiling technologies. However, there are still major gaps in our understanding of the mechanisms utilized by breast cancer cells to colonize the brain microenvironment, thus our arsenal of therapies remains relatively nonspecific, and the prognosis for breast cancer patients with BM remains poor. Additional insights into these mechanisms are necessary to facilitate the development of new preventive and curative therapeutic regimens to block this fatal disease. This paper aims to provide a general overview for the readers of what has been achieved in this field of research and its translation into clinical practice to date and to highlight exciting new areas of research that promise to inform the development of new targeted therapies for BM

Lithium attenuated the depressant and anxiogenic effect of juvenile social stress through mitigating the negative impact of interlukin-1β and nitric oxide on hypothala...

Abstract—The neuroimmune-endocrine dysfunction has been accepted as one of fundamental mechanisms contributing to the pathophysiology of psychiatric disorders including depression and anxiety. In this study, we aimed to evaluate the involvement of hypothalamic–pituitary–adre nal (HPA) axis, interleukin-1b, and nitrergic system in mediating the negative behavioral impacts of juvenile social isolation stress (SIS) in male mice. We also investigated the possible protective effects of lithium on behavioral and neurochemical changes in socially isolated animals. Results showed that experiencing 4-weeks of juvenile SIS provoked depressive and anxiety-like behaviors that were associated with hyper responsiveness of HPA axis, upregulation of interleukin-1b, and nitric oxide (NO) overproduction in the pre-frontal cortex and hippocampus. Administration of lithium (10 mg/kg) significantly attenuated the depressant and anxiogenic effects of SIS in behavioral tests. Lithium also restored the negative effects of SIS on cortical and hippocampal interleukin-1b and NO as well as HPA axis deregulation. Unlike the neutralizing effects of L-arginine (NO precursor), administration of L-NAME (3 mg/kg) and aminoguanidine (20 mg/kg) potentiated the positive effects of lithium on the behavioral and neurochemical profile of isolated mice. In conclusion, our results revealed that juvenile SIS-induced behavioral deficits are associated with abnormalities in HPA-immune function. Also, we suggest that alleviating effects of lithium on behavioral profile of isolated mice may be partly mediated by mitigating the negative impact of NO on HPA-immune function. � 2015 IBRO. Published by Elsevier Ltd. All rights reserve

NF-κB-dependent mechanism of action of c-Myc inhibitor 10058-F4: Highlighting a promising effect of c-Myc inhibition in Leukemia cells, irrespective of p53 status

Due to the frequent contribution in the pathogenesis of different human malignancies, c-Myc is among those transcription factors that are believed to be pharmacologically targeted for cancer therapeutic approaches. In the present study, we examined the anti-leukemic effect of a well-known c-Myc inhibitor 10058-F4 on a panel of hematologic malignant cells harboring either mutant or wild-type p53. Notably, we found that the suppression of c-Myc was coupled with the reduction in the survival of all the tested leukemic cells; however, as far as we are aware, this study suggests for the first time that the cytotoxic effect of 10058-F4 was not significantly affected by the molecular status of p53. Delving into the molecular mechanisms of the inhibitor in the most sensitive cell line revealed that 10058-F4 could induce apoptotic cell death in mutant p53-expressing NB4 cells through the suppression of NF-κB pathway coupled with a significant induction of intracellular reactive oxygen species (ROS). In addition, we found that the anti-leukemic effect of 10058-F4 was overshadowed, at least partially, through the compensatory activation of the PI3K signaling pathway; highlighting a plausible attenuating role of this axis on 10058-F4 cytotoxicity. In conclusion, the results of the present study shed light on the favorable anti-leukemic effect of 10058-F4, especially in combination with PI3K inhibitors in acute promyelocytic leukemia; however, further investigations should be accomplished to determine the efficacy of the inhibitor, either as a single agent or in a combined-modal strategy, in leukemia treatment. © 2020, Iranian Journal of Pharmaceutical Research. All rights reserved

Bibbia, cristianesimo e letteratura italiana: uno sguardo d'assieme.

L'A. ripercorre la presenza della Bibbia nella letteratura italiana dalle origini ai giorni nostri, sottolineando la persistenza della ripresa del Sacro testo sia nella poesia che nella prosa

The Effects of Arsenic Trioxide and Zoledronic Acid on Malignant Plasma Cells Derived from Bone Marrow Cells of Multiple Myeloma Patients

"nBackground: Multiple myeloma (MM) is a disease of plasma cells that has fatal consequences. New agents associated with mo­lecular targets have prompted clinical investigators to design new treatment strategies initially for advanced MM and later for newly diagnosed MM, with encouraging preliminary results.  We devised a project to assess the mechanisms of ac­tion of two drugs, Ar­senic trioxide (ATO) and Zoledronic acid (Zometa) on Bone marrow mononuclear cells (BMMCs) de­rived from patients."nMethods: Bone marrow samples were collected from 10 patients after receipt of formal consent. BMMCs were collected from samples. In two parallel sets of experiments, BMMCs were treated with 0.5, 2, 6 µM ATO and 0.1, 10, 100 µM Zo­meta, for 72 h. The following analyses were then performed on treated cells as compared to untreated cells (assumed as con­trol): cytotoxicity using Micro culture tetrazolium test (MTT assay); matrix metalloproteinase-2 zymography; comparative gene expression analysis of IL-6, vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-l)."nResults: MTT assay showed significant proliferation inhibition in ATO high dose treatment (6 uM). However, no signifi­cant in­hibitory effect of Zometa was seen. Zymography analyses showed significant decrease in gelatinolytic activity in treated cells. Analyses of gene expression using Real-Time RT-PCR methodology showed significant decrease in IL-6, ICAM-1, and VEGF genes as normalized against Hypoxanthine phosphoribosyltransferase normalizer and as compared with untreated cells."nConclusion: Both ATO and Zometa could significantly decrease MM cells critical phenotype and genotype. This finding could support the hypothesis that ATO or Zometa could inhibit growth and metastasis of malignant cells

Abrogation of histone deacetylases (HDACs) decreases survival of chronic myeloid leukemia cells: New insight into attenuating effects of the PI3K/c-Myc axis on panobinostat cytotoxicity

Although the identification of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of many cancer types including chronic myeloid leukemia (CML), still adjustment of neoplastic cells to cytotoxic effects of anticancer drugs is a serious challenge. In the area of drug resistance, epigenetic alterations are at the center of attention and the present study aimed to evaluate whether blockage of epigenetics mechanisms using a pan-histone deacetylase (HDAC) inhibitor induces cell death in CML-derived K562 cells. We found that the abrogation of HDACs using panobinostat resulted in a reduction in survival of the K562 cell line through p27-mediated cell cycle arrest. Noteworthy, the results of the synergistic experiments revealed that HDAC suppression could be recruited as a way to potentiate cytotoxicity of Imatinib and to enhance the therapeutic efficacy of CML. Here, we proposed for the first time that the inhibitory effect of panobinostat was overshadowed, at least partially, through the aberrant activation of the phosphoinositide 3-kinase (PI3K)/c-Myc axis. Meanwhile, we found that upon blockage of autophagy and the proteasome pathway, as the main axis involved in the activation of autophagy, the anti-leukemic property of the HDAC inhibitor was potentiated. Taken together, our study suggests the beneficial application of HDAC inhibition in the treatment strategies of CML; however, further in vivo studies are needed to determine the efficacy of this inhibitor, either as a single agent or in combination with small molecule inhibitors of PI3K and/or c-Myc in this malignancy. © 2021 International Federation for Cell Biolog

Abrogation of histone deacetylases (HDACs) decreases survival of chronic myeloid leukemia cells: New insight into attenuating effects of the PI3K/c-Myc axis on panobinostat cytotoxicity

Although the identification of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of many cancer types including chronic myeloid leukemia (CML), still adjustment of neoplastic cells to cytotoxic effects of anticancer drugs is a serious challenge. In the area of drug resistance, epigenetic alterations are at the center of attention and the present study aimed to evaluate whether blockage of epigenetics mechanisms using a pan-histone deacetylase (HDAC) inhibitor induces cell death in CML-derived K562 cells. We found that the abrogation of HDACs using panobinostat resulted in a reduction in survival of the K562 cell line through p27-mediated cell cycle arrest. Noteworthy, the results of the synergistic experiments revealed that HDAC suppression could be recruited as a way to potentiate cytotoxicity of Imatinib and to enhance the therapeutic efficacy of CML. Here, we proposed for the first time that the inhibitory effect of panobinostat was overshadowed, at least partially, through the aberrant activation of the phosphoinositide 3-kinase (PI3K)/c-Myc axis. Meanwhile, we found that upon blockage of autophagy and the proteasome pathway, as the main axis involved in the activation of autophagy, the anti-leukemic property of the HDAC inhibitor was potentiated. Taken together, our study suggests the beneficial application of HDAC inhibition in the treatment strategies of CML; however, further in vivo studies are needed to determine the efficacy of this inhibitor, either as a single agent or in combination with small molecule inhibitors of PI3K and/or c-Myc in this malignancy. © 2021 International Federation for Cell Biolog

Arsenic trioxide induces cell cycle arrest and alters DNA methylation patterns of cell cycle regulatory genes in colorectal cancer cells

Aims Cell cycle dysregulation is important in tumorigenesis. Transcriptional silencing of cell cycle regulatory genes, due to DNA methylation, is a common epigenetic event in malignancies. As2O3 has been shown to induce cell cycle arrest and also to be a potential hypomethylating agent. Our study aimed to investigate DNA methylation patterns of cell cycle regulatory genes promoters, the effects of Arsenic trioxide (As2O3) on the methylated genes and cell cycle distribution in colorectal cancer (CRC) cell lines. Main methods The methylation-specific PCR (MSP) and/or restriction enzyme-based methods were used to study the promoter methylation patterns of 24 cell cycle regulatory genes in CRC cell lines. Gene expression level and cell cycle distribution were determined by Real-time PCR and flow cytometric analyses, respectively. Key findings Our methylation analysis indicated that only promoters of RBL1 (p107), CHFR and p16 genes were aberrantly methylated in three cell lines. As2O3 significantly decreased DNA methylation in promoter regions of these genes and restored their expression. We found that As2O3 significantly reduced the expression of DNA methyltransferase 1 (DNMT1) and increased arsenic methyltransferase (AS3MT). Furthermore, As2O3 altered transcriptional activity of several unmethylated cell cycle regulatory genes including cyclin B1, E1, D1, GADD45A and p21. Cell cycle flow cytometry analysis showed As2O3 induced G2/M arrest in all three cell lines. Significance These data suggest that demethylation and alteration in the expression level of the cell cycle-related genes may be possible mechanisms in As2O3-induced cell cycle arrest in colorectal cancer cells. � 2016 Elsevier Inc