Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adhesion is a hallmark of haematological and solid cancer cells. All five classes of cell adhesion molecules (CAM) - integrins, cadherins, immunoglobulin-like CAMs, selectins and CD44s - are characteristically dysregulated in human cancer. Adhesion enables and promotes cancer-defining biological processes like growth, survival, migration, extravasation, homing, and metastasis. Furthermore, cell adhesion mediates drug resistance (CAM-DR) in multiple myeloma, malignant lymphoma, acute and chronic leukaemias, as well as in pancreatic cancer, neuroblastoma, small cell and non-small cell lung cancer, mesothelioma, colorectal carcinoma, and breast cancer. Cell adhesion protects from death by radiation, genotoxic chemotherapy, or targeted pathway inhibitors. Adhesion molecules are overexpressed on drug resistant cells (e.g. multiple myeloma or prostate cancer). Very recently, several cell adhesion mediated survival pathways have been elucidated, with key mediators being LFA-1, VLA-4, FAK, ILK, Src, PI3K, Akt, Ras, MEK, Erk, HMG-CoA reductase, Rho, Rho kinase, PKC, and NFkB. Because the surface and the intracellular targets are now known and because specific compounds are becoming increasingly available, first clinical trials regarding ANTI-ADHESION therapies are ongoing. However, in comparison to the comprehensive preclinical and clinical knowledge about CAMs, the number of drugs developed thusfar is quite low. ANTI-ADHESION strategies include targeting of surface antigens, inhibition of cell adhesion associated pathways, inhibition of CAM-DR, and targeted drug delivery. As ANTI-ADHESION is based on general characteristics of cancer cells independent of specific disease entities or treatment modalities, it may become a successful, low-toxic and broadly applicable concept in cancer treatment.
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PMID:ANTI-ADHESION evolves to a promising therapeutic concept in oncology. 1839 55

The mechanism by which the glucocorticoid (GC) dexamethasone induces apoptosis in multiple myeloma (MM) cells is unknown, although previous work suggests that either transactivation through the glucocorticoid response element (GRE), transrepression of NF-kappaB, phosphorylation of RAFTK (Pyk2), or induction of Bim is important. We studied this question by ectopically expressing mutant glucocorticoid receptors (GRs) in the dexamethasone-resistant MM1R cell line, which has lost its GR. Lentiviral-mediated reexpression of wild-type GR restored GRE transactivation, NF-kappaB transrepression, RAFTK phosphorylation, Bim induction, and dexamethasone-induced apoptosis. We then reexpressed 4 GR mutants, each possessing various molecular effects, into MM1R cells. A perfect correlation was present between induction of GRE transactivation and induction of apoptosis. In contrast, NF-kappaB transrepression and RAFTK phosphorylation were not required for apoptosis. Although not required for dexamethasone-mediated apoptosis, NF-kappaB inhibition achieved by gene transfer suggested that NF-kappaB transrepression could contribute to apoptosis in dexamethasone-treated cells. Dexamethasone treatment of MM1R cells expressing a mutant incapable of inducing apoptosis successfully resulted in RAFTK (Pyk2) phosphorylation and Bim induction indicating the latter GR-mediated events were not sufficient to induce apoptosis. MM1R cells expressing mutant GRs will be helpful in defining the molecular mechanisms of dexamethasone-induced apoptosis of myeloma cells.
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PMID:Dexamethasone-induced apoptotic mechanisms in myeloma cells investigated by analysis of mutant glucocorticoid receptors. 1851 58

Today several monoclonal antibodies, including the anti-CD20 antibody (rituximab), the anti-CD52 antibody (alemtuzumab) and the anti-CD33 antibody (gemtuzumab ozogamacin) are all integrated in the therapeutic armamentarium of patients with malignant lymphoma, chronic lymphocytic leukaemia and acute myelogenous leukaemia, respectively. Rituximab has also been shown to be highly effective in the treatment of refractory autoimmune haemolytic anemias, idiopathic thrombocytopenia, and relapsing thrombotic thrombocytopenic purpura. New signal transduction inhibitors, dasatinib and nilotinib, are being used in patients with chronic myelogeneous leukaemia who develop resistance to imatinib. Thalidomide, lenalidomide and bortezomib have all been shown to be highly effective in multiple myeloma, and JAK2-inhibitors have entered phase II studies of patients with JAK2-positive primary myelofibrosis and related diseases.
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PMID:[Novel medical treatment modalities in hematology]. 1856 91

The aim of the current study is to determine whether butein (3,4,2',4'-tetrahydroxychalcone) exhibits antiproliferative effects against tumor cells through suppression of the signal transducer and activator of transcription 3 (STAT3) activation pathway. We investigated the effects of butein on constitutive and inducible STAT3 activation, role of tyrosine kinases and phosphatases in STAT3 activation, STAT3-regulated gene products, and growth modulation of tumor cells. We found that this chalcone inhibited both constitutive and interleukin-6-inducible STAT3 activation in multiple myeloma (MM) cells. The suppression was mediated through the inhibition of activation of the upstream kinases c-Src, Janus-like kinase (JAK) 1, and JAK2. Vanadate treatment reversed the butein-induced down-regulation of STAT3 activation, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that butein induced the expression of the tyrosine phosphatase SHP-1 and deletion of SHP-1 gene by small interfering RNA abolished the ability of butein to inhibit STAT3 activation, suggesting the critical role of SHP-1 in the action of this chalcone. Butein down-regulated the expression of STAT3-regulated gene products such as Bcl-xL, Bcl-2, cyclin D1, and Mcl-1, and this led to the suppression of proliferation and induction of apoptosis. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the butein-induced apoptosis. Moreover, we found that butein significantly potentiated the apoptotic effects of thalidomide and Velcade in MM cells. Overall, these results suggest that butein is a novel blocker of STAT3 activation and thus may have potential in suppression of tumor cell proliferation and reversal of chemoresistance in MM cells.
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PMID:Butein suppresses constitutive and inducible signal transducer and activator of transcription (STAT) 3 activation and STAT3-regulated gene products through the induction of a protein tyrosine phosphatase SHP-1. 1910 60

Heat shock protein 90 (HSP90) is a ubiquitously expressed chaperone that is involved in the posttranslational folding and stability of proteins. Inhibition at the NH(2)-terminal ATP-binding site leads to the degradation of client proteins by the ubiquitin proteasome pathway. Inhibition of HSP90 leads to the degradation of known oncogenes, such as ERB-B2, BRAF, and BCR-ABL, leading to the combinatorial blockade of multiple signal transduction pathways, such as the RAS-RAF-mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase and phosphatidylinositol 3-kinase pathways. Multiple structurally diverse HSP90 inhibitors are undergoing early clinical evaluation. The clinical focus of these drugs should be solid tumors, such as breast, prostate, and lung cancers, along with malignant melanoma, in addition to hematologic malignancies, such as chronic myeloid leukemia and multiple myeloma. HSP90 inhibitors can be used as single agents or in combination with other targeted treatments or conventional forms of treatment such as chemotherapy and radiotherapy. Clinical trials evaluating efficacy of these agents should include innovative designs to capture cytostasis evidenced by clinical nonprogression and enrichment of patient populations by molecular characterization. The results of clinical trials evaluating the efficacy of drugs targeting this exciting target are awaited.
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PMID:Heat shock protein 90 as a drug target: some like it hot. 1911 27

Hematopoietic malignancies include leukemia, lymphoma and multiple myeloma. These diseases are primarily diagnosed on the basis of morphological features of affected cells, which appear in peripheral blood, bone marrow and lymphoid organs. By taking advantage of the repetitive accessibility of the neoplastic cells within the peripheral blood / and/or bone marrow aspirates, morphological tests are conducted not only for diagnosis but also for evaluation of clinical outcomes and prognosis, suggesting that the morphological features are considered as a clinical biomarker in hematopoietic malignancies. However, remarkable progress in molecular targeted therapy and allogeneic hematopoietic stem cell transplantation has improved the long-term prognosis of patients with hematopoietic malignancies, and some patients are curable. Under such modern strategies for therapy, monitoring of minimal residual disease(MRD), which is morphologically undetectable, is required to guide proper management of the disease by evaluation of an optimal response to therapy and early detection of disease relapse. At present, both immunophenotypes(surface markers)and chimeric fusion genes(e. g. BCR-ABL in chronic myeloid leukemia)characteristic of hematopoietic malignant cells are analyzed as clinically useful biomarkers to monitor MRD by two highly sensitive methods, multiparameter flow cytometry and real-time quantitative PCR, respectively. On the other hand, serum markers reflecting the size of the tumor mass are clinically available to monitor the disease progression in mass-forming hematopoietic malignancies: e. g., soluble IL-2 receptor for lymphoma and M-protein or free light chain for multiple myeloma.
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PMID:[Clinical values of biomarkers in hematopoietic malignancies]. 1915 62

SRC (steroid receptor co-activator)-1 has been reported to interact with and to be an essential co-activator for several members of the STAT (signal transducer and activator of transcription) family, including STAT3, the major signal transducer of IL (interleukin)-6. We addressed the question of whether SRC-1 is crucial for IL-6- and STAT3-mediated physiological responses such as myeloma cell survival and acute-phase protein induction. In fact, silencing of SRC-1 by RNA interference rapidly induced apoptosis in IL-6-dependent INA-6 human myeloma cells, comparable with what was observed upon silencing of STAT3. Using chromatin immunoprecipitation at STAT3 target regions of various genes, however, we observed constitutive binding of SRC-1 that decreased when INA-6 cells were treated with IL-6. The same held true for STAT3 target genes analysed in HepG2 human hepatocellular carcinoma cells. SRC-1-knockdown studies demonstrated that STAT3-controlled promoters require neither SRC-1 nor the other p160 family members SRC-2 or SRC-3 in HepG2 cells. Furthermore, microarray expression profiling demonstrated that the responsiveness of IL-6 target genes is not affected by SRC-1 silencing. In contrast, co-activators of the CBP [CREB (cAMP-response element-binding protein)-binding protein]/p300 family proved functionally important for the transactivation potential of STAT3 and bound inducibly to STAT3 target regions. This recruitment did not depend on the presence of SRC-1. Altogether, this suggests that functional impairment of STAT3 is not involved in the induction of myeloma cell apoptosis by SRC-1 silencing. We therefore conclude that STAT3 transactivates its target genes by the recruitment of CBP/p300 co-activators and that this process generally does not require the contribution of SRC-1.
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PMID:Co-activator SRC-1 is dispensable for transcriptional control by STAT3. 1920 49

The interaction of multiple myeloma (MM) cells with the bone marrow (BM) milieu plays a crucial role in MM pathogenesis. Stromal cell-derived factor-1 (SDF1) regulates homing of MM cells to the BM. In this study, we examined the role of RhoA and Rac1 GTPases in SDF1-induced adhesion and chemotaxis of MM. We found that both RhoA and Rac1 play key roles in SDF1-induced adhesion of MM cells to BM stromal cells, whereas RhoA was involved in chemotaxis and motility. Furthermore, both ROCK and Rac1 inhibitors reduced SDF1-induced polymerization of actin and activation of LIMK, SRC, FAK, and cofilin. Moreover, RhoA and Rac1 reduced homing of MM cells to BM niches. In conclusion, we characterized the role of RhoA and Rac1 GTPases in SDF1-induced adhesion, chemotaxis, and homing of MM cells to the BM, providing the framework for targeting RhoA and Rac1 GTPases as novel MM therapy.
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PMID:RhoA and Rac1 GTPases play major and differential roles in stromal cell-derived factor-1-induced cell adhesion and chemotaxis in multiple myeloma. 1944 61

Cytogenetic response (CyR), especially complete CyR (CCyR), has historically and is currently associated with a significant survival advantage in patients with chronic-phase chronic myeloid leukemia (CP-CML). CCyR represents a critical level of disease reduction irrespective of treatment type, and timely achievement demonstrates treatment-sensitive disease. Guidelines from European LeukemiaNet and the National Comprehensive Cancer Network therefore state that alternative therapies should be considered for patients not achieving CCyR by 6 or 12 months. Data from clinical trials indicate that early CCyR affords the best benefit:risk ratio by minimizing the mounting risk of disease progression, and the duration of CCyR when achieved affects disease progression. Treatment options for patients who fail to achieve CCyR on standard-dose imatinib (400 mg/day) include imatinib dose escalation, dasatinib, nilotinib, stem-cell transplantation, or a clinical trial. While molecular testing gauges further risk reduction, disease stability, and often elimination of BCR-ABL transcripts below detection threshold, CCyR remains the most important surrogate for long-term survival and cytogenetic testing remains a key part of patient care in the management of CML, particularly early in response. Longerterm follow-up data will be required to confirm CCyR as a surrogate marker for survival in imatinib-resistant patients treated with the secondgeneration tyrosine kinase inhibitors, dasatinib and nilotinib.
Clin Lymphoma Myeloma 2009 Jun
PMID:Response dynamics in chronic-phase chronic myeloid leukemia. 1952 90

The identification of proliferation/survival pathways constitutively activated by genetic alterations in multiple myeloma (MM), or sustained by the bone marrow (BM) microenvironment, provides novel opportunities for the development of targeted therapies. The deregulated function of protein tyrosine kinases plays a critical role in driving MM malignant phenotype. We investigated the effects of the multi-target tyrosine kinase inhibitor RPI-1 in a panel of human MM cell lines, including t(4;14) positive cell lines expressing the TK receptor FGF-R3. Cells harboring FGF-R3 activating mutations (KMS11 and OPM2) displayed the highest sensitivity to RPI-1 antiproliferative effect. The stimulating effect of the aFGF ligand was abrogated in cells harboring a non-constitutively active receptor. Drug treatment inhibited activation and expression of the FGF-R3(Y373C) mutant as well as aFGF-dependent signaling involving AKT and ERKs. Inhibition of JAK2, an additional RPI-1 target, resulted in STAT3 inactivation. Blockade of these proliferation/survival pathways was associated with caspase-dependent apoptosis. Moreover, drug treatment abrogated proliferative and pro-invasive stimuli provided by conditioned medium from mesenchymal stromal cells. Gene expression profile of KMS11 cells showed 22 upregulated and 52 downregulated genes upon RPI-1 treatment, with an early modulation of genes implicated in MM pathobiology such as SAT-1, MYC, MIP-1alpha/beta, FGF-R3, and the growth factor receptor B-cell maturation antigen (BCMA). Thus, concomitant blockade of FGF-R3 and JAK2 results in inhibition of several MM-promoting pathways, including BCMA-regulated signaling, and downregulation of disease-associated proteins. These data may have therapeutic implications in the design of treatment strategies resulting in the concomitant inhibition of FGF-R3 and JAK2 signaling pathways in t(4;14) MM.
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PMID:Concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, JAK2 and BCMA in human multiple myeloma cells by multi-kinase targeting. 1955 70


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