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

Human CD38 is a nonlineage-restricted type II transmembrane glycoprotein that has emerged as a multifunctional protein in recent years. It can serve as an ectoenzyme that catalyzes the synthesis and hydrolysis of cyclic ADP-ribose, a recently identified Ca2+ mobilizing agent that acts independently of inositol triphosphate. The enzymatic functions of CD38 probably contribute to an array of its immunoregulatory functions. The release of soluble CD38 and the ability of membrane-bound CD38 to become internalized in response to appropriate stimuli suggest that extracellular and intracellular roles for this protein are equally plausible. Ligation of CD38 with agonistic antibodies induces diverse effects in hematopoietic cells that range from growth stimulation to induction and prevention from apoptosis, induction of cytokines, activation of kinases, and phosphorylation of certain proteins. These observations suggest that CD38 may serve as receptor for an as yet unidentified ligand. Other molecules that share significant structural and functional homology to CD38 have been identified in humans and mice, suggesting that these molecules may represent a new family of proteins. Understanding the role of CD38 in certain pathological conditions such as myeloma, X-linked agammaglobulinemia, and HIV infection may provide insight into its physiological functions.
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PMID:Human CD38, a cell-surface protein with multiple functions. 890 11

Human CD38 is a transmembrane glycoprotein involved in lymphocyte activation and adhesion to endothelium. The ectocellular domain of the molecule possesses properties of a bifunctional enzyme catalyzing both the synthesis from NAD+ and the hydrolysis of the calcium-releasing metabolite cyclic ADP-ribose (cADPR). Surface expression of CD38 (mCD38) is rapidly and almost completely down-modulated upon ligation by specific mAb in cells from different lineages. The data presented here also show that, in addition to the existence of a mCD38, a soluble form of CD38 (sCD38) is detectable in the cell culture supernatant of allo-activated T lymphocytes and of several tumor cell lines. sCD38 is also present in vivo and is assayable in normal (fetal serum and amniotic fluid) and pathological (serum and ascites from patients with multiple myeloma, and serum from patients with AIDS) biological fluids. Immunoaffinity chromatography, SDS-PAGE and Western blot analyses with mAb and polyclonal antibodies, along with metabolic labeling, yield a body of data concerning the structure of sCD38, which displays a M(r) of 39 kDa. Native sCD38 maintains the ability to inhibit the binding activity of different anti-CD38 mAb and still catalyzes the synthesis and the hydrolysis of cADPR at the same ratio observed with mCD38. Furthermore, cross-linking experiments indicate that the purified soluble molecule binds a 120 kDa molecule expressed by monocytoid cells and identified as a candidate ligand for human mCD38.
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PMID:Identification and characterization of an active soluble form of human CD38 in normal and pathological fluids. 894 58

The poly(ADP-ribose)polymerase (PADPRP) gene has been implicated in carcinogenesis through its role in DNA repair, replication and recombination. A two-allele polymorphism in the chromosome 13 PADPRP pseudogene has been studied in several racial groups. It has been suggested that the B allele, which results from a 193-bp deletion in the gene, predisposes to myeloma in Blacks. We assessed the association between chromosome 13 PADPRP pseudogene genotype, mutagen sensitivity (a marker reflecting host DNA repair capability), cigarette smoking, and lung cancer risk in a minority lung cancer case-control study. The chromosome 13 PADPRP pseudogene polymorphism was detected by polymerase chain reaction-based analysis. Mutagen sensitivity was measured by an in vitro assay that quantified bleomycin-induced chromatid breaks in peripheral blood lymphocyte cultures. We examined 121 cases (80 African-Americans and 41 Mexican-Americans) with previously untreated lung cancer and 171 matched controls. Our results suggested that the distribution of the PADPRP pseudogene genotype frequencies was significantly different among African-American and Mexican-American controls (P < 0.001). The susceptibility genotype (i.e. at least one B allele) was found in 82.5% of African-American cases, 79.4% of African-American controls, 53.7% of Mexican-American cases, and 32.4% of Mexican-American controls. The odds ratios (OR) and 95% confidence intervals for the PADPRP susceptibility genotypes were 2.3 (95% CI = 0.7-8.0) and 3.2 (95% CI = 1.0-10.3) for African-Americans and Mexican-Americans respectively, after adjustment by age, sex, pack-years and mutagen sensitivity. Patients with the susceptibility genotype appeared to have more mutagen-induced breaks than did patients with the other genotype. Only adenocarcinoma was significantly associated with the PADPRP susceptibility genotype (OR = 3.8). Mutagen sensitivity (> or = 1 break/cell) was significantly associated with lung cancer risk for both ethnic groups with increased ORs of above three-fold. On stratified analysis, synergistic interactions were noted for the PADPRP susceptibility genotype, mutagen sensitivity and smoking status. In Mexican-Americans, the ORs for PADPRP susceptibility genotype, mutagen sensitivity and both risk factors combined were 1.3, 2.7 and 17.1 respectively. The combined OR for the PADPRP susceptibility genotype and smoking status was 15.6. Therefore, this polymorphism appears to be associated with lung cancer risk. However, it is likely that no single genotype is sufficiently predictive of risk and that a panel of susceptibility markers is needed to define the high-risk subgroup.
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PMID:Deletion in poly(ADP-ribose)polymerase pseudogene and lung cancer risk. 947 99

Irradiation of human ovarian carcinoma cells (OVCAR 3) and myeloma cells (RPMI 8226) with graded doses of 137Cs-gamma-rays led to a 35-40% increase in time-dependent apoptosis 72 hr after 6-8 Gy irradiation. Large individual variations in sensitivity to radiation-induced apoptosis were noted in human lymphocytes obtained from 5 donors. Pretreatment of OVCAR 3 and RPMI 8226 cells with 0.01 Gy increased their resistance to apoptosis after subsequent 6 Gy irradiation several hours or 48 and 72 hr later. A dose of 4 or 8 Gy given in 2 equal fractions at an interval of a few hours produced a low level of apoptosis compared to that resulting from a single administration of the same total dose. Adaptive response was demonstrated in 2 out of 3 samples of human lymphocytes isolated from different donors, and no split-dose effect for apoptosis was noted in 2 other donors. In split-dose experiments, there was no correlation between the sensitivity of cells to apoptosis and their position in the cell cycle, after the first half-dose. No G1 block was observed in irradiated cell lines. Adaptive response and split-dose effect were prevented by 3-aminobenzamide and okadaic acid which inhibit poly(ADP-ribose)polymerase and protein phosphatase, respectively. These results imply a common mechanism for acquired resistance to radiation-induced apoptosis in adaptive response and the split-dose effect.
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PMID:Radiation-induced apoptosis in human tumor cell lines: adaptive response and split-dose effect. 963 97

PS-341 (bortezomib, Velcadetrade mark) is a promising novel agent for treatment of advanced multiple myeloma (MM); however, 65% of patients with relapsed refractory disease in a phase II study do not respond to PS-341. We have previously shown that lysophosphatidic acid acyltransferase (LPAAT)-beta inhibitor CT-32615 triggers caspase-dependent apoptosis, and can overcome resistance to conventional therapeutics (i.e., dexamethasone, doxorubicin, melphalan) in MM cells. In this study, we therefore determined whether CT-32615 could also overcome resistance to PS-341. We first characterized molecular mechanisms of resistance to PS-341 in DHL-4 cells. DHL-4 cells express low levels of caspase-3 and caspase-8; furthermore, no cleavage in caspase-8, caspase-9, caspase-3, poly ADP-ribose polymerase (PARP), or DNA fragmentation factor 45 was triggered by PS-341 treatment. We have previously shown that PS-341 treatment triggers phosphorylation of c-Jun NH(2)-terminal kinase (JNK), which subsequently induces caspase-dependent apoptosis; conversely, JNK inhibition blocks PS-341-induced apoptosis. We here show that phosphorylation of SEK-1, JNK, and c-Jun are not induced by PS-341 treatment, suggesting that PS-341 does not trigger a stress response in DHL-4 cells. Importantly, CT-32615 inhibits growth of DHL-4 cells in a time- and dose-dependent fashion: a transient G2/M cell cycle arrest induced by CT-32615 is mediated via downregulation of cdc25c and cdc2. CT-32615 triggered swelling and lysis of DHL-4 cells, without caspase/PARP cleavage or TUNEL-positivity, suggesting a necrotic response. Our studies therefore demonstrate that LPAAT-beta inhibitor CT-32615 triggers necrosis, even in PS-341-resistant DHL-4 cells, providing the framework for its evaluation to overcome clinical PS-341 resistance and improve patient outcome.
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PMID:Molecular characterization of PS-341 (bortezomib) resistance: implications for overcoming resistance using lysophosphatidic acid acyltransferase (LPAAT)-beta inhibitors. 1573 76

SGN-40, a humanized immoglobulin G1 (IgG1) anti-CD40 monoclonal antibody, mediates cytotoxicity against human multiple myeloma (MM) cells via suppression of interleukin (IL)-6-induced proliferative and antiapoptotic effects as well as antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we studied the clinical significance of an immunomodulatory drug lenalidomide on SGN-40-induced cytotoxicity against CD138(+)CD40(+) MM lines and patient MM cells. Pretreatment with lenalidomide sensitized MM cells to SGN-40-induced cell death. Combined lenalidomide and SGN-40 significantly induced MM apoptosis, evidenced by enhanced cleavage of caspase-3/8/poly(ADP-ribose)polymerase and increased sub-G(0) cells, compared with either single agent at the same doses. Pretreatment of effector cells with lenalidomide augmented SGN-40-induced MM cell lysis, associated with an increased number of CD56(+)CD3(-) natural killer (NK) cells expressing CD16 and LFA-1. Importantly, pretreatment with lenalidomide or lenalidomide and SGN-40 markedly enhanced NK-cell-mediated lysis of autologous patient MM cells triggered by SGN-40. Lenalidomide also up-regulated CD40L on CD56(+)CD3(-) NK cells, facilitating IL-2-mediated activation of NK cells. In addition, lenalidomide induced the CD56(dim) NK subset, which are more potent mediators of ADCC against target MM cells than the CD56(bright) NK subset. Finally, pretreatment of both effector and target MM cells with lenalidomide markedly enhanced SGN-40-mediated ADCC against CD40-expressing MM cells. These studies, therefore, show that the addition of lenalidomide to SGN-40 enhances cytotoxicity against MM cells, providing the framework for combined lenalidomide and SGN-40 in a new treatment paradigm to both target MM cells directly and induce immune effectors against MM.
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PMID:Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. 1635 83

Histone deacetylase (HDAC) inhibitors have shown cytotoxicity as single agents in preclinical studies for multiple myeloma (MM) cells. LBH589 is a novel hydroxamic acid derivative that at low nanomolar concentrations induces apoptosis in MM cells resistant to conventional therapies via caspase activation and poly-(ADP-ribose) polymerase (PARP) cleavage. Significant synergistic cytotoxicity was observed with LBH589 in combination with bortezomib against MM cells that were sensitive and resistant to dexamethasone (Dex), as well as primary patient MM cells. LBH589 at low nanomolar concentrations also induced alpha-tubulin hyperacetylation. Aggresome formation was observed in the presence of bortezomib, and the combination of LBH589 plus bortezomib induced the formation of abnormal bundles of hyeracetylated alpha-tubulin but with diminished aggresome size and apoptotic nuclei. These data confirm the potential clinical benefit of combining HDAC inhibitors with proteasome inhibitors, and provide insight into the mechanisms of synergistic anti-MM activity of bortezomib in combination with LBH589.
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PMID:Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. 1672 95

Multiple myeloma (MM) is an invariably fatal plasma cell malignancy, primarily due to the therapeutic resistance which ultimately arises. Much of the resistance results from the expression of various survival factors. Despite this, the ribonucleoside analogue, 8-chloro-adenosine (8-Cl-Ado), is cytotoxic to a number of MM cell lines. Previously, we established that the analogue incorporates into the RNA and inhibits mRNA synthesis. Because 8-Cl-Ado is able to overcome survival signals present in MM cells and inhibits mRNA synthesis, it is likely that the drug induces cytotoxicity by depleting the expression of critical MM survival genes. We investigated this question using gene array analysis, real-time reverse transcription-PCR, and immunoblot analysis on 8-Cl-Ado-treated MM.1S cells and found that the mRNA and protein levels of the receptor tyrosine kinase MET decrease prior to apoptosis. To determine MET's role in 8-Cl-Ado cytotoxicity, we generated MM.1S clones stably expressing a MET ribozyme. None of the clones expressed <25% of the basal levels of MET mRNA, suggesting that a threshold level of MET is necessary for their survival. Additionally, the ribozyme knockdown lines were more sensitive to the cytotoxic actions of 8-Cl-Ado as caspase-3 activation and the induction of poly-ADP-ribose polymerase (PARP) cleavage were more pronounced and evident 12 h earlier than in the parental cells. We further established MET's role in MM cell survival by demonstrating that a retroviral MET RNA interference construct induces PARP cleavage in MM.1S cells. These results show that MET provides a survival mechanism for MM cells. 8-Cl-Ado overcomes MM cell survival by a mechanism that involves the depletion of MET.
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PMID:Multiple myeloma cell killing by depletion of the MET receptor tyrosine kinase. 1794 23

In the present study, the effects of lidamycin (LDM), a member of the enediyne antibiotic family, on two human multiple myeloma (MM) cell lines, U266 and SKO-007, were evaluated. In MTS assay, LDM showed much more potent cytotoxicity than conventional anti-MM agents to both cell lines. The IC(50) values of LDM for the U266 and SKO-007 cells were 0.0575 +/- 0.0015 and 0.1585 +/- 0.0166 nM, respectively, much lower than those of adriamycin, dexamethasone, and vincristine. Mechanistically, LDM triggered MM cells apoptosis by increasing the levels of cleaved poly ADP-ribose polymerase (PARP) and caspase-3/7. In addition, activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) was a critical mediator in LDM-induced cell death. Inhibition of the expression of p38 MAPK and JNK by pharmacological inhibitors reversed the LDM-induced apoptosis through decreasing the level of cleaved PARP and caspase-3/7. Interestingly, phosphorylation of extracellular signal-related kinase was increased by LDM; conversely, MEK inhibitor synergistically enhanced LDM-induced cytotoxicity and apoptosis in MM cells. The results demonstrated that LDM suppresses MM cell growth through the activation of p38 MAPK and JNK, with the potential to be developed as a chemotherapeutic agent for MM.
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PMID:Enediyne lidamycin induces apoptosis in human multiple myeloma cells through activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase. 1946 99

Nuclear factor-kappaB (NF-kappaB) is involved in multiple aspects of oncogenesis and controls cancer cell survival by promoting anti-apoptotic gene expression. The constitutive activation of NF-kappaB in several types of cancers, including hematological malignancies, has been implicated in the resistance to chemo- and radiation therapy. We have previously reported that cytokine- or virus-induced NF-kappaB activation is inhibited by chemical and physical inducers of the heat shock response (HSR). In this study we show that heat stress inhibits constitutive NF-kappaB DNA-binding activity in different types of B-cell malignancies, including multiple myeloma, activated B-cell-like (ABC) type of diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma presenting aberrant NF-kappaB regulation. Heat-induced NF-kappaB inhibition leads to rapid downregulation of the anti-apoptotic protein cellular inhibitor-of-apoptosis protein 2 (cIAP-2), followed by activation of caspase-3 and cleavage of the caspase-3 substrate poly(adenosine diphosphate ribose)polymerase (PARP), causing massive apoptosis under conditions that do not affect viability in cells not presenting NF-kappaB aberrations. NF-kappaB inhibition by the proteasome inhibitor bortezomib and by short-hairpin RNA (shRNA) interference results in increased sensitivity of HS-Sultan B-cell lymphoma to hyperthermic stress. Altogether, the results indicate that aggressive B-cell malignancies presenting constitutive NF-kappaB activity are sensitive to heat-induced apoptosis, and suggest that aberrant NF-kappaB regulation may be a marker of heat stress sensitivity in cancer cells.
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PMID:Heat stress triggers apoptosis by impairing NF-kappaB survival signaling in malignant B cells. 1992 45


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