Deregulation of Ion Channel and Transporter Encoding Genes in Pediatric Gliomas

Brain tumors, including the majority gliomas, are the leading cause of cancer-related death in children. World Health Organization has divided pediatric brain tumors into different grades and, based upon cDNA microarray data identifying gene expression profiles (GEPs), it has become evident in the last decade that the various grades involve different types of genetic alterations. However, it is not known whether ion channel and transporter genes, intimately involved in brain functioning, are associated with such GEPs. We determined the GEPs in an available cohort of 10 pediatric brain tumors initially by comparing the data obtained from four primary tumor samples and corresponding short-term cultures. The correspondence between the two types of samples was statistically significant. We then performed bioinformatic analyses on those samples (a total of nine) which corresponded to tumors of glial origin, either tissues or cell cultures, depending on the best “RNA integrity number.” We used R software to evaluate the genes which were differentially expressed (DE) in gliomas compared with normal brain. Applying a p-value below 0.01 and fold change ≥4, led to identification of 2284 DE genes. Through a Functional Annotation Analysis (FAA) using the NIH-DAVID software, the DE genes turned out to be associated mainly with: immune/inflammatory response, cell proliferation and survival, cell adhesion and motility, neuronal phenotype, and ion transport. We have shown that GEPs of pediatric brain tumors can be studied using either primary tumor samples or short-term cultures with similar results. From FAA, we concluded that, among DE genes, pediatric gliomas show a strong deregulation of genes related to ion channels and transporters

hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma

BACKGROUND: hERG1 channels are aberrantly expressed in human cancers. The expression, functional role and clinical significance of hERG1 channels in pancreatic ductal adenocarcinoma (PDAC) is lacking. METHODS: hERG1 expression was tested in PDAC primary samples assembled as tissue microarray by immunohistochemistry using an anti-hERG1 monoclonal antibody (α-hERG1-MoAb). The functional role of hERG1 was studied in PDAC cell lines and primary cultures. ERG1 expression during PDAC progression was studied in Pdx-1-Cre,LSL-Kras(G12D/+),LSL-Trp53(R175H/+) transgenic (KPC) mice. ERG1 expression in vivo was determined by optical imaging using Alexa-680-labelled α-hERG1-MoAb. RESULTS: (i) hERG1 was expressed at high levels in 59% of primary PDAC; (ii) hERG1 blockade decreased PDAC cell growth and migration; (iii) hERG1 was physically and functionally linked to the Epidermal Growth Factor-Receptor pathway; (iv) in transgenic mice, ERG1 was expressed in PanIN lesions, reaching high expression levels in PDAC; (v) PDAC patients whose primary tumour showed high hERG1 expression had a worse prognosis; (vi) the α-hERG1-MoAb could detect PDAC in vivo. CONCLUSIONS: hERG1 regulates PDAC malignancy and its expression, once validated in a larger cohort also comprising of late-stage, non-surgically resected cases, may be exploited for diagnostic and prognostic purposes in PDAC either ex vivo or in vivo

New Pyrimido-Indole Compound CD-160130 Preferentially Inhibits the K V

K(V)11.1 (hERG1) channels are often overexpressed in human cancers. In leukemias, K(V)11.1 regulates pro-survival signals that promote resistance to chemotherapy, raising the possibility that inhibitors of K(V)11.1 could be therapeutically beneficial. However, because of the role of K(V)11.1 in cardiac repolarization, blocking these channels may cause cardiac arrhythmias. We show that CD-160130, a novel pyrimido-indole compound, blocks K(V)11.1 channels with a higher efficacy for the K(V)11.1 isoform B, in which the IC50 (1.8 mu M) was approximately 10-fold lower than observed in K(V)11.1 isoform A. At this concentration, CD-160130 also had minor effects on K(ir)2.1, K-V 1.3, K(v)1.5, and K(Ca)3.1. In vitro, CD-160130 induced leukemia cell apoptosis, and could overcome bone marrow mesenchymal stromal cell (MSC)-induced chemoresistance. This effect was caused by interference with the survival signaling pathways triggered by MSCs. In vivo, CD-160130 produced an antileukemic activity, stronger than that caused by cytarabine. Consistent with its atypical target specificity, CD-160130 did not bind to the main binding site of the arrhythmogenic K(V)11.1 blockers (the Phe656 pore residue). Importantly, in guinea pigs CD-160130 produced neither alteration of the cardiac action potential shape in dissociated cardiomyocytes nor any lengthening of the QT interval in vivo. Moreover, CD-160130 had no myelotoxicity on human bone marrow-derived cells. Therefore, CD-160130 is a promising first-in-class compound to attempt oncologic therapy without cardiotoxicity, based on targeting K(V)11.1. Because leukemia and cardiac cells tend to express different ratios of the A and B K(V)11.1 isoforms, the pharmacological properties of CD-160130 may depend, at least in part, on isoform specificity

Deterministic and stochastic aspects of VEGF-A production and the cooperative behavior of tumoral cell colony

International audienceA model is proposed to study the process of hypoxia-induced angiogenesis in cancer cells. The model accounts for the role played by the vascular endothelial growth factor (VEGF)-A in regulating the oxygen intake. VEGF-A is dynamically controlled by the HIF-1α concentration. If not degraded, HIF-1α can bind to the subunit termed HIF-1β and so experience translocation to the nucleus, to exert its proper transcriptional activity. The delicate balance between these opposing tendencies translates into the emergence of distinct macroscopic behaviors in terms of the associated molecular concentrations that we here trace back to normoxia, hypoxia and death regimes. These aspects are firstly analyzed with reference to the ideal mean-field scenario. Stochastic fluctuations are also briefly discussed and shown to seed a cooperative interaction among cellular units, competing for the same oxygen reservoir

The New Pyrimido-indole Compound CD-160130 Preferentially Inhibits the KV11.1B Isoform and Produces Antileukemic Effects Without Cardio-toxicity

K(V)11.1 (hERG1) channels are often overexpressed in human cancers. In leukemias, K(V)11.1 regulates pro-survival signals that promote resistance to chemotherapy, raising the possibility that inhibitors of K(V)11.1 could be therapeutically beneficial. However, because of the role of K(V)11.1 in cardiac repolarization, blocking these channels may cause cardiac arrhythmias. We show that CD-160130, a novel pyrimido-indole compound, blocks K(V)11.1 channels with a higher efficacy for the K(V)11.1 isoform B, in which the IC50 (1.8 mu M) was approximately 10-fold lower than observed in K(V)11.1 isoform A. At this concentration, CD-160130 also had minor effects on K(ir)2.1, K-V 1.3, K(v)1.5, and K(Ca)3.1. In vitro, CD-160130 induced leukemia cell apoptosis, and could overcome bone marrow mesenchymal stromal cell (MSC)-induced chemoresistance. This effect was caused by interference with the survival signaling pathways triggered by MSCs. In vivo, CD-160130 produced an antileukemic activity, stronger than that caused by cytarabine. Consistent with its atypical target specificity, CD-160130 did not bind to the main binding site of the arrhythmogenic K(V)11.1 blockers (the Phe656 pore residue). Importantly, in guinea pigs CD-160130 produced neither alteration of the cardiac action potential shape in dissociated cardiomyocytes nor any lengthening of the QT interval in vivo. Moreover, CD-160130 had no myelotoxicity on human bone marrow-derived cells. Therefore, CD-160130 is a promising first-in-class compound to attempt oncologic therapy without cardiotoxicity, based on targeting K(V)11.1. Because leukemia and cardiac cells tend to express different ratios of the A and B K(V)11.1 isoforms, the pharmacological properties of CD-160130 may depend, at least in part, on isoform specificity