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)

The molecular chaperone heat shock protein 90 (Hsp90) serves essential roles in the regulation of signaling protein function, trafficking, and turnover. Hsp90 function is intimately linked to intrinsic ATP binding and hydrolysis activities, the latter of which is under the regulatory control of accessory factors. Glucose-regulated protein of 94 kDa (GRP94), the endoplasmic reticulum Hsp90, is highly homologous to cytosolic Hsp90. However, neither accessory factors nor adenosine nucleotides have been clearly implicated in the regulation of GRP94-client protein interactions. In the current study, the structural and regulatory consequences of adenosine nucleotide binding to GRP94 were investigated. We report that apo-GRP94 undergoes a time- and temperature-dependent tertiary conformational change that exposes a site(s) of protein-protein interaction; ATP, ADP, and radicicol markedly suppress this conformational change. In concert with these findings, ATP and ADP act identically to suppress GRP94 homooligomerization, as well as both local and global conformational activity. To identify a role(s) for ATP or ADP in the regulation of GRP94-client protein interactions, immunoglobulin (Ig) heavy chain folding intermediates containing bound GRP94 and immunoglobulin binding protein (BiP) were isolated from myeloma cells, and the effects of adenosine nucleotides on chaperone-Ig heavy chain interactions were examined. Whereas ATP elicited efficient release of BiP from both wild-type and mutant Ig heavy chain intermediates, GRP94 remained in stable association with Ig heavy chains in the presence of ATP or ADP. On the basis of these data, we propose that structural maturation of the client protein substrate, rather than ATP binding or hydrolysis, serves as the primary signal for dissociation of GRP94-client protein complexes.
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PMID:Adenosine nucleotides and the regulation of GRP94-client protein interactions. 1523 92

Most anticancer chemotherapies are immunosuppressive and induce nonimmunogenic tumor cell death. Bortezomib, a specific inhibitor of 26S proteasome, has shown clinical activity in several human tumors, including myeloma. Here we show that the uptake of human myeloma cells by dendritic cells (DCs) after tumor cell death by bortezomib, but not gamma irradiation or steroids, leads to the induction of antitumor immunity, including against primary tumor cells, without the need for any additional adjuvants. The delivery of activating signal from bortezomib-killed tumor cells to DCs depends on cell-cell contact between DCs and dying tumor cells and is mediated by bortezomib-induced exposure of heat shock protein 90 (hsp90) on the surface of dying cells. The combination of bortezomib and geldanamycin (an hsp90 inhibitor) leads to greater apoptosis of tumor cells but abrogates their immunogenicity. These data identify drug-induced exposure of endogenous heat shock proteins on the surface of dying cells as a mechanism of immunogenic death of human tumors. Specific targeting of bortezomib to tumors may enhance their immunogenicity and the induction of antitumor immunity.
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PMID:Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. 1729 90

Plasma cells producing high levels of paraprotein are dependent on the unfolded protein response (UPR) and chaperone proteins to ensure correct protein folding and cell survival. We hypothesized that disrupting client-chaperone interactions using heat shock protein 90 (Hsp90) inhibitors would result in an inability to handle immunoglobulin production with the induction of the UPR and myeloma cell death. To study this, myeloma cells were treated with Hsp90 inhibitors as well as known endoplasmic reticulum stress inducers and proteasome inhibitors. Treatment with thapsigargin and tunicamycin led to the activation of all 3 branches of the UPR, with early splicing of XBP1 indicative of IRE1 activation, upregulation of CHOP consistent with ER resident kinase (PERK) activation, and activating transcription factor 6 (ATF6) splicing. 17-AAG and radicicol also induced splicing of XBP1, with the induction of CHOP and activation of ATF6, whereas bortezomib resulted in the induction of CHOP and activation of ATF6 with minimal effects on XBP1. After treatment with all drugs, expression levels of the molecular chaperones BiP and GRP94 were increased. All drugs inhibited proliferation and induced cell death with activation of JNK and caspase cleavage. In conclusion, Hsp90 inhibitors induce myeloma cell death at least in part via endoplasmic reticulum stress and the UPR death pathway.
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PMID:Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells. 1752 89

The ultimate goal of most anti-tumor therapies is to kill tumor cells. While most of the attention in cancer therapy has been towards enhancing the death of tumor cells, the effect of dying tumors on the immune system has been less studied. Recent studies have suggested that cell death induced by different agents may have distinct consequences for the immune system. One of the immunogenic signals may be the expression of heat shock proteins on dying tumor cells under certain settings. For example, bortezomib(a proteasome inhibitor) induces the expression of heat shock protein 90 (hsp90) on the surface of dying human myeloma tumor cells. Recognition of such tumor cells by antigen presenting dendritic cells leads to the generation of anti-tumor T cells. Harnessing the properties of some anti-tumor agents to induce immunogenic death of tumor cells may facilitate the recruitment of adaptive immunity and promote the durability of anti-tumor effects.
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PMID:Towards a better way to die with chemotherapy: role of heat shock protein exposure on dying tumor cells. 1772 Oct 82

Within the last decade, several novel classes of anti-myeloma therapeutics have become available. The clinical successes achieved by thalidomide, lenalidomide, and the proteasome inhibitor bortezomib, and in particular the ability of these agents to lead to major clinical responses in patients resistant to conventional or high-dose chemotherapy, have highlighted the importance of expanding further the spectrum of classes of agents utilized for the treatment of myeloma. Herein, we review the current status for the development of novel anti-myeloma agents, with emphasis on classes of therapeutics which have already translated into clinical trials or those in advanced stages of preclinical development. These include second-generation proteasome inhibitors (NPI-0052 and PR-171), heat shock protein 90 (hsp90) inhibitors, 2-methoxyestradiol, histone deacetylase (HDAC) inhibitors (e.g. SAHA and LBH589), fibroblast growth factor receptor 3 (FGF-R3) inhibitors, insulin-like growth factor 1 receptor (IGF-1R) inhibitors, mTOR inhibitors, monoclonal antibodies, and agents specifically targeting the tumor microenvironment, such as defibrotide.
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PMID:From the bench to the bedside: emerging new treatments in multiple myeloma. 1807 Jul 20

The successful clinical development of thalidomide, bortezomib, and lenalidomide not only transformed the therapeutic management of multiple myeloma (MM) but also catalyzed a renewed interest in the development of additional classes of novel agents for this disease. This review focuses on a series of new therapeutics that have shown promising preclinical results, as well as encouraging safety profiles and early evidence of anti-MM activity in clinical studies, either alone or in combination with other, conventional or novel, anti-MM treatments. These agents include second-generation proteasome inhibitors and immunomodulatory agents, as well as members of other therapeutic classes, such as histone deacetylase inhibitors (HDAC), heat shock protein 90 (Hsp90) inhibitors, and the alkylphospholipid Akt inhibitor perifosine.
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PMID:Emerging treatments for multiple myeloma: beyond immunomodulatory drugs and bortezomib. 1938

A paucity of validated kinase targets in human multiple myeloma has delayed clinical deployment of kinase inhibitors in treatment strategies. We therefore conducted a kinome-wide small interfering RNA (siRNA) lethality study in myeloma tumor lines bearing common t(4;14), t(14;16), and t(11;14) translocations to identify critically vulnerable kinases in myeloma tumor cells without regard to preconceived mechanistic notions. Fifteen kinases were repeatedly vulnerable in myeloma cells, including AKT1, AK3L1, AURKA, AURKB, CDC2L1, CDK5R2, FES, FLT4, GAK, GRK6, HK1, PKN1, PLK1, SMG1, and TNK2. Whereas several kinases (PLK1, HK1) were equally vulnerable in epithelial cells, others and particularly G protein-coupled receptor kinase, GRK6, appeared selectively vulnerable in myeloma. GRK6 inhibition was lethal to 6 of 7 myeloma tumor lines but was tolerated in 7 of 7 human cell lines. GRK6 exhibits lymphoid-restricted expression, and from coimmunoprecipitation studies we demonstrate that expression in myeloma cells is regulated via direct association with the heat shock protein 90 (HSP90) chaperone. GRK6 silencing causes suppression of signal transducer and activator of transcription 3 (STAT3) phosphorylation associated with reduction in MCL1 levels and phosphorylation, illustrating a potent mechanism for the cytotoxicity of GRK6 inhibition in multiple myeloma (MM) tumor cells. As mice that lack GRK6 are healthy, inhibition of GRK6 represents a uniquely targeted novel therapeutic strategy in human multiple myeloma.
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PMID:Kinome-wide RNAi studies in human multiple myeloma identify vulnerable kinase targets, including a lymphoid-restricted kinase, GRK6. 1999 89

The past decade has witnessed a dramatic improvement in the therapeutic options in multiple myeloma (MM). Several novel biologically targeted agents are in clinical use and have resulted in improved outcomes. However, the disease remains incurable, underscoring the need for continued efforts towards understanding MM biology, better risk stratification and exploitation of novel therapeutic approaches. Novel agents that target tumor and stromal compartments can be categorized as those that target protein dynamics (e.g., heat shock protein 90 and the ubiquitin-proteasome system), intracellular signaling kinases (e.g., JAK/STAT, PI3k/Akt/mTOR and MAPK pathways), cell cycle molecular machinery (e.g., cyclin-dependent kinase inhibitor and Aurora kinase inhibitors), membrane-bound receptors (e.g., IGF-1, VEGF and CD40), epigenetic modulators (e.g., DNA methyltransferase and histone deacetylase), tumor vasculature and microenvironment (e.g., angiogenesis and integrins) and agents modulating anti-MM immune responses. This article focuses on a series of new therapeutic targets that have shown promising preclinical results and early evidence of anti-MM activity in clinical studies, either alone or in combination with other conventional or novel anti-MM treatments.
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PMID:Novel therapeutic targets for multiple myeloma. 2022 97

This study was aimed to investigate the correlation of heat shock protein 90 (HSP90) expression with migration ability of human multiple myeloma cells. The HSP90 mRNA expression and migration change of human multiple myeloma cell line (U266) were detected by RT-PCR and Transwell chamber respectively after treatment of U266 cells with final concentration 50, 100, 150, 200 nmol/L of bortezomib (proteosome inhibitor) for 4 hours. The results indicated that along with the increasing of bortezomib concentration, the expression level of HSP90alpha mRNA in U266 cells was enhanced, while no obvious increase of HSP90beta mRNA expression was observed in spite of statistical difference as a whole (p<0.05), but with the increasing of drug concentration in cells, their migration ability gradually decreased (p<0.05). It is concluded that the correlation of HSP90 expression with migration ability of human multiple myeloma cells exists.
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PMID:[Correlation of HSP90 mRNA expression with migration ability of human multiple myeloma cells]. 2041 71

Tanespimycin (17-allylamino-17-demethoxygeldanamycin, 17-AAG) disrupts heat shock protein 90 (HSP90), a key molecular chaperone for signal transduction proteins critical to myeloma growth, survival and drug resistance. In previous studies, tanespimycin monotherapy was well tolerated and active in heavily pretreated patients with relapsed/refractory multiple myeloma (MM). Preclinical data have shown antitumour synergy between tanespimycin and bortezomib, with more pronounced intracellular accumulation of ubiquitinated proteins than either drug alone, an effect attributed to the synergistic suppression of chymotryptic activity in the 20S proteasome. HSP70 induction has been observed in all Phase 1 tanespimycin studies in which it has been measured, with several separate reports of HSP70 overexpression protecting against peripheral nerve injury. In this Phase 2, open-label multicentre study, we compared 1.3 mg/m2 bortezomib + three doses of tanespimycin: 50, 175 and 340 mg/m2 in heavily pretreated patients with relapsed and refractory MM and measured HSP70 expression and proteasome activity levels in plasma of treated patients. The study was closed prematurely for resource-based reasons, precluding dose comparison. Nonetheless, antitumour activity was observed, with promising response rates and promising severity of peripheral neuropathy.
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PMID:Tanespimycin with bortezomib: activity in relapsed/refractory patients with multiple myeloma. 2061 38


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