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)

The proteasome is responsible for the degradation of intracellular proteins, including several involved in cell cycle control and the regulation of apoptosis. Preclinical studies have shown that the proteasome inhibitor bortezomib decreases proliferation, induces apoptosis, enhances the activity of chemotherapy and radiation, and reverses chemoresistance in a variety of hematologic and solid malignancy models in vitro and in vivo. Proteasome inhibition with bortezomib has specifically promoted apoptosis of tumor cells through the stabilization of p53, p21, p27, Bax, and IkappaBalpha, resulting in nuclear factor kappaB inhibition. Bortezomib was the first proteasome inhibitor to enter clinical trials. In two Phase II trials, SUMMIT and CREST, it was found that treatment with bortezomib, alone or in combination with dexamethasone, produced durable responses with meaningful survival benefits in patients with recurrent and/or refractory multiple myeloma. In the APEX Phase III trial, bortezomib produced significant survival benefits and improved response rates over high-dose dexamethasone at first recurrence and beyond in patients with multiple myeloma. Clinical trials evaluating the safety and activity of bortezomib alone or in combination regimens with dexamethasone, doxorubicin, melphalan, prednisone, and/or thalidomide in the treatment of patients with newly diagnosed multiple myeloma have shown encouraging results. Preliminary studies suggest that bortezomib may serve as induction therapy before stem cell transplantation. Proteasome inhibition with bortezomib also has shown activity with manageable toxicity in mantle cell and other lymphomas, leukemias, and solid malignancies, including nonsmall cell lung carcinoma. Further studies with bortezomib as monotherapy and in combination regimens in the treatment of solid and hematologic malignancies are warranted.
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PMID:Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies. 1617 3

Proteasome-mediated proteolysis is a mechanism for mediating important regulatory proteins within the cell. Proteins that have been targeted for degradation by the proteasome are convalently tagged with a poly-ubiquitin protein chain prior to be recognized by the 19S subunit of proteasome. This degradation system controls the expression of a wide variety of cellular targets including tumor suppressors such as p53, inhibitor of nuclear factor NFkappaB, cyclin-dependent kinase inhibitors such as p21 and p27. Because of these functions, the proteasome has become a new target for cancer treatment. The potent and selective proteasome inhibitor, PS-341 or Velcade was approved in the United States and launched in may 2003 for the treatment of multiple myeloma patients who have received at least two prior therapies. On April 2004, the European commission granted marketing authorization for Velcade with the same indication. The same year 2004, the Nobel Prize in chemistry was awarded to three researchers "for the discovery of ubitiquin-mediated protein degradation", a regulated process by which proteins are cleaved into peptides inside cells.
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PMID:[A new therapy with bortezomib, an oncologic medicinal product of the year 2004]. 1638 84

The aim of this study was to evaluate the effects of valproic acid (VPA), as a histone deacetylase inhibitor, on myeloma cell lines and on sorted human bone marrow multiple myeloma cells. VPA induced accumulation of acetylated histones, potently inhibited proliferation in a dose-dependent manner and induced apoptosis in all myeloma cell lines tested as well as in sorted primary multiple myeloma cells. Cell cycle analysis indicated an arrest in G0/1 phase in response to VPA. Accumulation of p21 and reduced levels of cyclin D1 were detected. The production of vascular endothelial growth factor was significantly inhibited by VPA. These results provide the framework for clinical trials.
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PMID:The effects of the histone deacetylase inhibitor valproic acid on cell cycle, growth suppression and apoptosis in multiple myeloma. 1646 12

Dysregulation of cyclin D1 expression is one of the most common genetic aberrations found in hematopoietic malignancies, including multiple myeloma. To address the effects of cyclin D1 overexpression might have on the response of malignant hematopoietic cells to CDK inhibitors, the impact of ectopic cyclin D1 overexpression on the response of human multiple myeloma U266 cells to various cyclin-dependent kinase (CDK) inhibitors was examined. Cyclin D1 overexpression markedly increased the apoptotic response of cells to the CDK inhibitors flavopiridol, roscovitine, and R-roscovitine. Ectopic expression of cyclin D1 resulted in p21(CIP1) accumulation, an effect that was diminished by CDK inhibitor exposure. In pRb-null U266 cells, enforced overexpression of cyclin D1 diminished CDK inhibitor-mediated dephosphorylation of the pocket proteins p130 and p107, reduced binding of E2F1 and E2F4 to p130 and p107, and attenuated inhibition of E2F activity. Notably, CDK inhibitors failed to reduce the S phase fraction in cyclin D1/U266 cells in contrast to effects in their wild-type counterparts. Finally, cyclin D1/U266 cells exhibited diminished basal NF-kappaB activity compared to controls, which was essentially completely abrogated by CDK inhibitor exposure. Together, these findings suggest that dysregulation of cyclin D1 sensitizes human myeloma cells to the actions of CDK inhibitors through mechanisms involving interference with p21(CIP1) expression, dephosphorylation of pocket proteins and inactivation of E2Fs culminating in S phase entry, as well as inactivation of NF-kappaB, leading to apoptosis rather than growth arrest.
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PMID:Cyclin D1 overexpression increases the susceptibility of human U266 myeloma cells to CDK inhibitors through a process involving p130-, p107- and E2F-dependent S phase entry. 1647 54

Because multiple myeloma remains associated with a poor prognosis, novel drugs targeting specific signaling pathways are needed. The efficacy of selective estrogen receptor modulators for the treatment of multiple myeloma is not well documented. In the present report, we studied the antitumor activity of raloxifene, a selective estrogen receptor modulator, on multiple myeloma cell lines. Raloxifene effects were assessed by tetrazolium salt reduction assay, cell cycle analysis, and Western blotting. Mobility shift assay, immunoprecipitation, chromatin immunoprecipitation assay, and gene expression profiling were performed to characterize the mechanisms of raloxifene-induced activity. Indeed, raloxifene, as well as tamoxifen, decreased JJN-3 and U266 myeloma cell viability and induced caspase-dependent apoptosis. Raloxifene and tamoxifen also increased the cytotoxic response to vincristine and arsenic trioxide. Moreover, raloxifene inhibited constitutive nuclear factor-kappaB (NF-kappaB) activity in myeloma cells by removing p65 from its binding sites through estrogen receptor alpha interaction with p65. It is noteworthy that microarray analysis showed that raloxifene treatment decreased the expression of known NF-kappaB-regulated genes involved in myeloma cell survival and myeloma-induced bone lesions (e.g., c-myc, mip-1alpha, hgf, pac1,...) and induced the expression of a subset of genes regulating cellular cycle (e.g., p21, gadd34, cyclin G2,...). In conclusion, raloxifene induces myeloma cell cycle arrest and apoptosis partly through NF-kappaB-dependent mechanisms. These findings also provide a transcriptional profile of raloxifene treatment on multiple myeloma cells, offering the framework for future studies of selective estrogen receptor modulators therapy in multiple myeloma.
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PMID:Raloxifene-induced myeloma cell apoptosis: a study of nuclear factor-kappaB inhibition and gene expression signature. 1649 77

Multiple myeloma represents an incurable disease, for which development of new therapies is required. Here, we report the effect on myeloma cells of LBH589, a new hydroxamic acid-derived histone deacetylase inhibitor. LBH589 was a potent antimyeloma agent (IC(50) < 40 nmol/L) on both cell lines and fresh cells from multiple myeloma patients, including cells resistant to conventional chemotherapeutic agents. In addition, LBH589 potentiated the action of drugs, such as bortezomib, dexamethasone, or melphalan. Using gene array, quantitative PCR, and Western analyses, we observed that LBH589 affected a large number of genes involved in cell cycle and cell death pathways. LBH589 blocked cell cycle progression, and this was accompanied by p21, p53, and p57 up-regulation. LBH589 induced cell death through an increase in the mitochondrial outer membrane permeability. LBH589 favored apoptosome formation by inducing cytochrome c release, Apaf-1 up-regulation, and caspase-9 cleavage. In addition, LBH589 stimulated a caspase-independent pathway through the release of AIF from the mitochondria. LBH589 down-regulated Bcl-2 and particularly Bcl-X. Moreover, overexpression of Bcl-X in multiple myeloma cells prevented LBH589-induced cell death. All these data indicate that LBH589 could be a useful drug for the treatment of multiple myeloma patients.
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PMID:The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance. 1674 Jul 17

Rice protein isolate (RPI) has been reported to reduce the incidence of 7,12-dimethylbenz[a]anthracene-induced mammary tumors in rats. To determine the potential role of phytochemicals associated with the RPI, we studied in vitro antitumor activities of an ether fraction from RPI using human tumor cell lines, including two human breast carcinoma cell lines (MDA-MB-453 and MCF-7) and two myeloma cell lines (RPMI-8226 and IM-9). Concentration-dependent antiproliferative effects of the ether fraction were observed in all cell lines using the standard 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Fraction-induced apoptosis (P < 0.05) was detected in all cell lines, and this was associated with the induction of proapoptotic bax protein and cdk inhibitors (p21) and the suppression of cdk4 and cyclin D1 activity. Liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) with both positive and negative modes was used to analyze the phytochemicals in the ether fraction from RPI. Fifty-seven phytochemicals were identified or characterized by their diagnostic fragmentation patterns and direct comparison with the authentic standards on the basis of electrospray ionization-MS/MS data. The major components bound to RPI were lysoglycerophospholipids, fatty acids, and fatty acid 3-[2-(2,3-dihydroxy-propoxycarbonyl)-2-hydroxy-ethoxy]-2-hydroxy-propyl esters.
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PMID:In vitro actions on human cancer cells and the liquid chromatography-mass spectrometry/mass spectrometry fingerprint of phytochemicals in rice protein isolate. 1675 84

Studies in our laboratory demonstrate that vitamin D (1,25 dihydroxycholecalciferol or calcitriol) has significant antitumor activity in vitro and in vivo in murine and human squamous cell, prostate, lung, pancreatic and myeloma model systems. Calcitriol induces G0/G1 arrest, modulates p27 and p21, the cyclin-dependent kinase (cdk) inhibitors implicated in G1 arrest, and induces cleavage of caspase 3, PARP and the mitogen-activated protein kinase (MEK) in a caspase-dependent manner. Calcitriol also decreases phospho-Erk (P-Erk) and phospho-Akt (P-Akt), kinases that regulate cell survival pathways and up-regulate the pro-apoptotic signaling molecule, MEKK-1. Glucocorticoids enhance calcitriol-mediated activities pre-clinically in vitro and in vivo. Dexamethasone (dex) significantly potentiated the antitumor effect of calcitriol and decreased calcitriol-induced hypercalcemia. Both in vitro and in vivo, dex increased vitamin D receptor (VDR) ligand binding in the tumor while decreasing binding in intestinal mucosa, the site of calcium absorption. These studies demonstrated that calcitriol has significant antiproliferative activity in a number of pre-clinical model systems and form the groundwork for on-going clinical studies investigating calcitriol as an anticancer agent.
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PMID:The antitumor efficacy of calcitriol: preclinical studies. 1688 62

Multiple Myeloma (MM) is a clonal B-cell malignancy affecting both the immune and the skeletal systems, and accounts for 10% of all hematological cancers. The immunomodulator ammonium trichloro (dioxoethylene-O,O') tellurate (AS101) is a non-toxic compound which has direct anti-tumoral properties in several tumor models. The present study examined the anti-tumoral activity of AS101 in MM by targeting the Akt/Survivin signaling pathway, crucial for survival. We showed that AS101 inhibites cell proliferation and colonies formation of MM cell lines, in a dose-dependent manner. AS101 induced G(2)/M growth arrest and increased both cyclin-dependent kinase inhibitor p21(waf1) protein levels and Cdk1 (p34(cdc2))-inhibitory phosphorylation. Longer incubation of MM cells with AS101 resulted in accumulation of apoptotic cell population and in increased caspase 9, 3 and 7 activities. We also showed that AS101 down-regulated Akt phosphorylation and decreased expression of the inhibitor of apoptosis, survivin. Since Akt and survivin are potentials targets for MM therapy, we suggest that AS101, currently being used in clinical studies, may have therapeutic implications in myeloma and other hematopoietic malignancies.
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PMID:The immunomodulator AS101 induces growth arrest and apoptosis in multiple myeloma: association with the Akt/survivin pathway. 1688 55

Bisphosphonates have been used to treat lytic lesions of multiple myeloma because of their inhibitory effects on osteoclasts. However, their effects on myeloma cells, per se, are not known to be correlated with specific markers. The goal of this study was to assess molecular concomitants of myeloma that might serve as markers for predicting the pharmacologic impact of bisphosphonates on malignant plasma cells. We tested the correlation of serum monoclonal immunoglobulin (Ig) level (IgG and IgA classes) with therapies utilizing two aminobisphosphonates, pamidronate (Aredia) and/or zoledronate (Zometa), in 19 patients with multiple myeloma. Myeloma cells from bone marrow biopsies were immunohistochemically stained for H-ras (p21 ras), N-ras, and the alpha subunit common to farnesyl and geranylgeranyl transferase (FTalpha/GGT alpha). Elevated expression level of H-ras in myeloma cells, rather than N-ras or FTalpha/GGTalpha, was significantly associated with a decrease of serum monoclonal Ig level following pamidronate treatment. The data suggest that pamidronate may have a direct inhibitory effect on the proliferation of myeloma cells, thus causing reduction in serum monoclonal Ig level. H-ras expression in myeloma cells may prove to be valuable in predicting the therapeutic effects of pamidronate.
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PMID:Morphoproteomic expression of H-ras (p21ras) correlates with serum monoclonal immunoglobulin reduction in multiple myeloma patients following pamidronate treatment. 1731 67


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