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 phosphatidylinositol 3-kinase (PI3-K)/mammalian target of rapamycin (mTOR) signal transduction pathway integrates signals from multiple receptor tyrosine kinases to control cell proliferation and survival. Key components of the pathway are the lipid kinase PI3-K, the small guanosine triphosphate-binding protein Rheb, and the protein kinases Akt and mTOR. Important natural inhibitors of the pathway include the lipid phosphatase PTEN and the tuberous sclerosis complex. Several components of this pathway are targeted by investigational antineoplastic agents. Rapamycin (sirolimus), the prototypic mTOR inhibitor, exhibits activity in acute myeloid leukemia. Three rapamycin analogs, temsirolimus, everolimus, and AP23573, are in clinical trials for various hematologic malignancies. Temsirolimus has produced a 38% overall response rate in relapsed mantle cell lymphoma, and AP23573 has demonstrated activity in acute leukemia. Everolimus is undergoing clinical testing in lymphoma (Hodgkin and non-Hodgkin) and multiple myeloma. In addition, perifosine, an inhibitor of Akt activation that exhibits substantial antimyeloma activity in preclinical models, is being examined in relapsed multiple myeloma. Based on results obtained to date, it appears that inhibitors of the PI3-K/mTOR pathway hold promise as single agents and in combination for hematologic malignancies.
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PMID:Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. 1691 89

Angiogenesis plays a significant role in a variety of malignant hematologic diseases, and it is recognized that it has prognostic value. However, the cellular mechanisms by which malignant hematologic cells induce angiogenesis are not well understood. In order to investigate the role of cells from B-cell chronic lymphocytic leukemia (B-CLL) and multiple myeloma (MM) in angiogenesis on human bone marrow endothelial cells (HBMEC), we analyzed the impact of factors secreted by B-CLL cells and by MM cells on HBMEC capillary tube formation on matrigel. It was found that, in addition to the secretion of angiogenic factors VEGF and b-FGF by B-CLL and MM cells, MM cells (but not B-CLL cells) induced a dramatic increase in expression of VEGFR-1 and VEGFR-3 on human bone marrow endothelial cells (HBMEC). It would seem that this increase in VEGFR-3 occurred via the ERK and mTOR pathways, since their respective inhibitors U0126, LY294002 or rapamycin were responsible for a decrease of VEGFR-3. In response to MM cells-increased VEGF receptors on HBMEC, endothelial cell migration was enhanced in a wound artificially produced in a semi-confluent HBMEC culture, a phenomenon which was also down-regulated by the same inhibitors that reversed the increase in VEGF receptors. The present study suggests that, in addition to the classic angiogenic pathway, another mechanism related to an increased expression of VEGFRs on HBMEC might exist in malignant hematopoietic angiogenesis.
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PMID:Malignant hematopoietic cells induce an increased expression of VEGFR-1 and VEGFR-3 on bone marrow endothelial cells via AKT and mTOR signalling pathways. 1695 14

We recently demonstrated that the mammalian target of rapamycin (mTOR) inhibitor, CCI-779, curtailed the growth of a subcutaneous challenge of multiple myeloma (MM) cells in immunodeficient mice. This antitumor effect was associated with prevention of cell proliferation, induction of apoptosis and inhibition of angiogenesis. Interestingly, myeloma tumors with heightened AKT activation were particularly sensitive to a CCI-779-induced antitumor response. To investigate whether part of the differential sensitivity was due to an AKT-regulated effect on angiogenesis, we compared the effects of mTOR inhibitors against isogenic MM cell lines that only differ by their degree of AKT activity. In this model, heightened AKT activity significantly sensitized MM cells to the following inhibitory effects of mTOR inhibition: angiogenesis in vivo, vascular endothelial growth factor (VEGF) expression in vitro and in vivo and VEGF translation (but not transcription). Assessment of p70S6 kinase activity indicated that rapamycin induced comparable mTOR inhibition in both cell lines suggesting that an adverse effect on VEGF cap-dependent translation would be comparable. Internal ribosome entry site (IRES)-mediated cap-independent translation is a salvage pathway for protein expression when mTOR is inhibited, so we analyzed a possible regulatory role of AKT on VEGF IRES activity. We found that elevated AKT activity inhibited VEGF IRES function. These results support a mechanism whereby AKT prevents VEGF IRES activity in myeloma cells during mTOR inhibition resulting in a more complete abrogation of VEGF translation, and ultimately, angiogenesis.
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PMID:AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cells. 1701 37

We studied antitumor effects of receptor tyrosine kinase inhibitor sunitinib (formerly SU11248) against a variety of hematologic malignancies including the following leukemias: eosinophilic (EOL-1), acute myeloid (THP-1, U937, Kasumi-1), biphenotypic (MV4-11), acute lymphoblastic (NALL-1, Jurkat, BALL-2, PALL-1, PALL-2), blast crisis of chronic myeloid (KU812, Kcl-22, K562), and adult T-cell (MT-1, MT-2, MT-4), as well as non-Hodgkin's lymphoma (KS-1, Dauji, Akata) and multiple myeloma (U266). Thymidine uptake studies showed that sunitinib was active against EOL-1, MV4-11, and Kasumi-1 cells, which possessed activating mutations of the PDGFRalpha, FLT-3, and c-KIT genes, respectively, with IC(50)s of <30 nmol/L. In addition, sunitinib inhibited the proliferation of freshly isolated leukemia cells from patients possessing mutations in FLT3 gene. Annexin V staining showed that sunitinib induced apoptosis of these cells. Sunitinib inhibited phosphorylation of FLT3 and PDGFRalpha in conjunction with blockade of mammalian target of rapamycin signaling in MV4-11 and EOL-1 cells, respectively. Interestingly, rapamycin analogue RAD001 enhanced the ability of sunitinib to inhibit the proliferation of leukemia cells and down-regulate levels of mammalian target of rapamycin effectors p70 S6 kinase and eukaryotic initiation factor 4E-binding protein 1 in these cells. Taken together, sunitinib may be useful for treatment of individuals with leukemias possessing activation mutation of tyrosine kinase, and the combination of sunitinib and RAD001 represents a promising novel treatment strategy.
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PMID:The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling. 1704 Oct 96

Multiple myeloma remains a fatal neoplasm and new treatments are urgently needed. In recent years, advances in understanding the molecular pathophysiology of myeloma and the mechanisms of drug resistance led to the development of several novel agents. The drugs with the most available clinical data are thalidomide, bortezomib and lenalidomide. Impressive results obtained with these agents - both in relapsed disease and in newly diagnosed patients - have significantly improved the outcome of myeloma patients. Several other new targeted agents are presently under investigation. These include monoclonal antibodies, agents that target mammalian target of rapamycin, histone acetylation, heat-shock proteins, growth factor signalling cascades, oncogenes, signal transducer and activators of the transcription pathway, Akt pathway and MAPK pathway. Their mechanisms of action, the available knowledge on their efficacy, safety and possible future clinical application are reviewed.
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PMID:Investigational treatments for multiple myeloma. 1710 82

Interferon-alpha (IFN-alpha) has been used for the last 20 years in the maintenance therapy of multiple myeloma (MM), though it is only effective in some patients. Congruent with this, IFN-alpha induces apoptosis in some MM cell lines. Understanding the mechanism of IFN-alpha-induced apoptosis could be useful in establishing criteria of eligibility for therapy. Here we show that IFN-alpha-induced apoptosis in the MM cell lines U266 and H929 was completely blocked by a specific inhibitor of Jak1. The mTOR inhibitor rapamycin mitigated apoptosis in U266 but potentiated it in H929 cells. IFN-alpha induced PS exposure, DeltaPsi(m) loss and pro-apoptotic conformational changes of Bak, but not of Bax, and was fully prevented by Mcl-1 overexpression in U266 cells. IFN-alpha treatment caused the release of cytochrome c from mitochondria to cytosol and consequently, a limited proteolytic processing of caspases. Apoptosis induced by IFN-alpha was only slightly prevented by caspase inhibitors. Levels of the BH3-only proteins PUMA and Bim increased during IFN-alpha treatment. Bim increase and apoptosis was prevented by transfection with the siRNA for Bim. PUMA-siRNA transfection reduced electroporation-induced apoptosis but had no effect on apoptosis triggered by IFN-alpha. The potentiating effect of rapamycin on apoptosis in H929 cells was associated to an increase in basal and IFN-alpha-induced Bim levels. Our results indicate that IFN-alpha causes apoptosis in myeloma cells through a moderate triggering of the mitochondrial route initiated by Bim and that mTOR inhibitors may be useful in IFN-alpha maintenance therapy of certain MM patients.
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PMID:Mechanism of apoptosis induced by IFN-alpha in human myeloma cells: role of Jak1 and Bim and potentiation by rapamycin. 1715 29

The role of adenosine monophosphate activated protein kinase (AMPK) in regulating multiple myeloma (MM) cell growth is not yet clear. In this study, we show that the AMPK activators 5-aminoimidazole-4-carboxamide riboside (AICAr) and D942 inhibit cell growth in MM cell lines. AICAr also induced an S-phase cell cycle arrest in all four tested cell lines and led to phosphorylation and thus activation of AMPK. Furthermore, the inhibition of a nucleoside transporter by nitrobenzyl-thio-9-beta-d-ribofuranosylpurine (NBTI), inhibition of the adenosine kinase by iodotubericidine and inhibition of AMPK by AMPKI Compound C reversed AICAr effects, indicating that the cellular effects of AICAr were mediated by AMPK. Activation of AMPK inhibited basal extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR) and P70S6 kinase (P70S6K) as well as AKT phosphorylation, and blocked IL-6, IGF-1, and HS-5 stromal cell conditioned medium-induced increase of cell growth. Troglitazone, which has previously been shown to activate AMPK, similarly inhibited MM cell growth, activated AMPK, and decreased ERK and P70S6K phosphorylation. Our results suggest that activation of AMPK inhibits MM cell growth despite stimulation with IL-6, IGF-1, or HS-5 stromal cell conditioned medium and represents a potential new target in the therapy of MM.
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PMID:Activation of adenosine monophosphate activated protein kinase inhibits growth of multiple myeloma cells. 1766 98

TSC1 and TSC2 are two recently identified tumor suppressor genes encoding hamartin and tuberin, respectively. They have been implicated in the pathogenesis of tuberous sclerosis, a neurological disorder linked with the development of hamartomas in numerous organs, including the brain, kidneys, heart, and liver. Both protein products of TSC1 and TSC2 form an intracellular complex exerting GTPase-activating (GAP) activity towards a small G protein Rheb (Ras homologue enriched in brain). Inhibition of Rheb is important for the positive regulation of mTOR pathway, while mutations of hamartin or tuberin result in uncontrolled cell cycle progression. Although the precise role for the TSC1/2 complex in tumor suppression is not clear, many studies have established a link with the regulation of transcription and protein biosynthesis, increasing susceptibility to apoptosis, cell differentiation, and cell cycle control. We describe the development of a monoclonal antibody specific towards TSC2/tuberin and characterize the suitability for Western blotting, immunoprecipitation, and immunofluorescent applications. The C-terminal region of TSC2 was expressed as a His-tag fusion protein in bacteria, affinity purified and used as an immunogen. Hybrid myelomas were produced from the spleenocytes of immunized mice and SP2/0 myeloma cells. Testing the specificity of cell culture supernatants from generated hybridomas towards recombinant His-TSC2C in ELISA assay allowed us to isolate a panel of positive clones. Further analysis of selected clones by Western blotting and immunoprecipitation revealed one clone, termed D6, which specifically recognized recombinant and endogenous TSC2. The specificity of generated antibody was also confirmed in TSC2(/) and TSC2(+/+) mouse embryo fibroblasts. In summary, the produced antibody is a useful tool in our research program and will be available for researchers investigating signal transduction pathways involving TSC1/2 signaling under physiological conditions and in human pathologies.
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PMID:Generation and characterization of monoclonal antibodies against tuberous sclerosis complex 2. 1772 89

Mantle cell lymphoma (MCL) still carries a poor prognosis. Chemoimmunotherapy (combination with rituximab) is the routine first-line therapy, although data strongly suggest a benefit from intensification through high-dose therapy with stem cell transplantation consolidation or dose-intense chemotherapy with HyperCVAD (fractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone)/rituximab. Unfortunately, most patients still experience relapse, and a multitude of novel agents are currently being tested in this setting, including proteasome inhibitors with bortezomib (the first of its class and first Food and Drug Administration-approved drug in MCL), mammalian target of rapamycin inhibitors, Bcl-2 inhibitors, and antiangiogenesis agents, among others. Because of the relative rarity of the disease-MCL represents 6% of non-Hodgkin lymphoma-an obvious effort is needed to enroll patients on clinical trials. Not surprisingly, as in other non-Hodgkin lymphomas, MCL appears more and more as a heterogeneous disease, which might impact future clinical trial design through pharmacogenomics and hopefully help us develop smaller "molecular" relevant trials.
Clin Lymphoma Myeloma 2007 Aug
PMID:Expanding therapeutic options in mantle cell lymphoma. 1787 43

The development of novel therapies for multiple myeloma depends on a comprehensive understanding of the events leading to cellular proliferation and survival. Controlling pathways that regulate growth signals is an emerging and complementary approach to myeloma treatment. The PI3K/Akt pathway is a central gatekeeper for crucial cellular functions including adhesion, angiogenesis, migration and development of drug resistance. Established proteins and genes such as mTOR, p53, NF-kappaB and BAD are all regulated through PI3K and Akt activation, making them attractive targets for broad downstream effects. Direct PI3K inhibition has demonstrated impressive tumor inhibition and regression in cell-line and animal models, and multiple agents including SF1126 are currently in clinical trials. Drugs such as perifosine that are specific for Akt are also in development. Combinations of these agents with existing therapies are rational approaches on the path to improving myeloma treatment.
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PMID:PI3 kinase/AKT pathway as a therapeutic target in multiple myeloma. 1804 16


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