Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was undertaken to estimate the therapeutic benefit to down-regulate the Na(+)/H(+) exchanger 1 (NHE1) for reversing chemoresistance of BCR-ABL-positive leukemia patient cells and cell lines. As a result, after treatment with specific NHE1 inhibitor Cariporide or high K(+) buffer to decrease intracellular pH (pH(i)), cells from relapsed patients exhibited decreased Pgp level, enhanced Rhodamine123 and drug accumulation, decreased colony-forming ability and the modulations of mitogen-activated protein kinases (MAPKs) activities. Furthermore, we used BCR-ABL-positive cell line K562 and its resistant counterparts K562/DOX and K562/G01 cell lines for further study. Together, these findings suggest that Pgp may be associated with the reversal of drug resistance in BCR-ABL-positive leukemia patients and cell lines by the inhibition of NHE1 though MAPK pathways.
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PMID:Reversal of Imatinib resistance in BCR-ABL-positive leukemia after inhibition of the Na+/H+ exchanger. 2157 1

Aberrant tyrosine kinase activity plays a critical role in many hematologic disorders, including chronic myeloid leukemia characterized by the constitutive activity of BCR-ABL. ABL therefore represents a crucial target for new therapeutic strategies. Here, we summarize the molecular pathways that are abnormally activated by the oncoprotein. Such pathways may provide additional opportunities to develop new drugs to overcome the resistance to tyrosine kinase inhibitors. In particular, the phosphoinositide 3-kinase (PI3K)/AKT pathway can be effectively blocked by mTOR inhibitors, and several compounds can hit the RAS pathway and the resulting mitogen-activated protein (MAP) extracellular signal-regulated kinase (ERK)1/2 (MEK) and MAP kinase activation. Furthermore, mitotic kinases can be blocked by Aurora kinase inhibitors, and Pim kinases can be blocked by selective serine-threonine kinase inhibitors. Finally, the abnormal pathways that sustain the self-renewal of leukemic stem cells are described as possible targets to completely eradicate leukemic clones. Such pathways include the Hedgehog pathway, which can be blocked by Smoothened inhibitors, and the CXCR4/SDF1 axis, which can be targeted by specific antagonists.
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PMID:Molecular pathways: BCR-ABL. 2215 49

Dasatinib, a multitargeted inhibitor of BCR-ABL and SRC kinases, exhibits antitumor activity and extends the survival of patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). However, some patients suffer from hepatotoxicity, which occurs through an unknown mechanism. In the present study, we found that Dasatinib could induce hepatotoxicity both in vitro and in vivo. Dasatinib reduced the cell viability of rat primary hepatocytes, induced the release of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) in vitro, and triggered the ballooning degeneration of hepatocytes in Sprague-Dawley rats in vivo. Apoptotic markers (chromatin condensation, cleaved caspase-3 and cleaved PARP) were detected to indicate that the injury induced by Dasatinib in hepatocytes in vitro was mediated by apoptosis. This result was further validated in vivo using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Here we found that Dasatinib dramatically increased the level of reactive oxygen species (ROS) in hepatocytes, reduced the intracellular glutathione (GSH) content, attenuated the activity of superoxide dismutase (SOD), generated malondialdehyde (MDA), a product of lipid peroxidation, decreased the mitochondrial membrane potential, and activated nuclear factor erythroid 2-related factor 2 (Nrf2) and mitogen-activated protein kinases (MAPK) related to oxidative stress and survival. These results confirm that oxidative stress plays a pivotal role in Dasatinib-mediated hepatotoxicity. N-acetylcysteine (NAC), a typical antioxidant, can scavenge free radicals, attenuate oxidative stress, and protect hepatocytes against Dasatinib-induced injury. Thus, relieving oxidative stress is a viable strategy for reducing Dasatinib-induced hepatotoxicity.
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PMID:Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes. 2253 70

Deletion of the DNA-binding domain of the transcription factor Ikaros generates dominant-negative isoforms that interfere with its activity and correlate with poor prognosis in human precursor B cell acute lymphoblastic leukemia (B-ALL). Here we found that conditional inactivation of the Ikaros DNA-binding domain in early pre-B cells arrested their differentiation at a stage at which integrin-dependent adhesion to niches augmented signaling via mitogen-activated protein kinases, proliferation and self-renewal and attenuated signaling via the pre-B cell signaling complex (pre-BCR) and the differentiation of pre-B cells. Transplantation of polyclonal Ikaros-mutant pre-B cells resulted in long-latency oligoclonal pre-B-ALL, which demonstrates that loss of Ikaros contributes to multistep B cell leukemogenesis. Our results explain how normal pre-B cells transit from a highly proliferative and stroma-dependent phase to a stroma-independent phase during which differentiation is enabled, and suggest potential therapeutic strategies for Ikaros-mutant B-ALL.
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PMID:Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre-B cells and progression to acute lymphoblastic leukemia. 2450 10

B-cell acute lymphoblastic lymphoma (B-ALL) is a disease found mainly in children and in young adults. B-ALL is characterized by the rapid proliferation of poorly differentiated lymphoid progenitor cells inside the bone marrow. In the United States, ~4,000 of these patients are diagnosed each year, accounting for ~30% of childhood cancer types. The tumorigenesis of the disease involves a number of abnormal gene expressions (including TEL-AML1, BCR-ABL-1, RAS and PI3K) leading to dysregulated cell cycle. Risk factors of B-ALL are the history of parvovirus B 19 infection, high birth weight and exposure to environmental toxins. These risk factors can induce abnormal DNA methylation and DNA damages. Treatment procedures are divided into three phases: Induction, consolidation and maintenance. The goal of treatment is complete remission without relapses. Apart from traditional treatments, newly developed approaches include gene targeting therapy, with the aim of wiping out leukemic cells through the inhibition of mitogen-activated protein kinases and via c-Myb inhibition enhancing sensitivity to chemotherapy. To evaluate the efficacy of ongoing treatments, several indicators are currently used. The indicators include the expression levels of microRNAs (miRs) miR-146a, miR-155, miR-181a and miR-195, and soluble interleukin 2 receptor. Multiple drug resistance and levels of glutathione reductase can affect treatment efficacy through the increased efflux of anti-cancer drugs and weakening the effect of chemotherapy through the reduction of intracellular reactive oxygen species. The present review appraised recent studies on B-ALL regarding its pathogenesis, risk factors, treatments, treatment evaluation and causes of disease relapse. Understanding the mechanisms of B-ALL initiation and causes of treatment failure can help physicians improve disease management and reduce relapses.
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PMID:Pathogenesis of pediatric B-cell acute lymphoblastic leukemia: Molecular pathways and disease treatments. 3256 69


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