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)

Multiple myeloma (MM) is an incurable B-cell malignancy, requiring new therapeutic strategies. We have found that synthetic alkyl-lysophospholipids (ALPs) edelfosine and perifosine induced apoptosis in MM cell lines and patient MM cells, whereas normal B and T lymphocytes were spared. ALPs induced recruitment of Fas/CD95 death receptor, Fas-associated death domain-containing protein, and procaspase-8 into lipid rafts, leading to the formation of the death-inducing signaling complex (DISC) and apoptosis. TNF-related apoptosis-inducing ligand receptor-1/death receptor 4 (TRAIL-R1/DR4) and TRAIL-R2/DR5, as well as Bid, were also recruited into lipid rafts, linking death receptor and mitochondrial signaling pathways. ALPs induced mitochondrial cytochrome c release. Bcl-X(L) overexpression prevented cytochrome c release and apoptosis. A Fas/CD95-deficient MM subline expressing DR4 and DR5 was resistant to edelfosine. Fas/CD95 retrovirus transduction bestowed edelfosine sensitivity in these cells. A Fas/CD95 mutant lacking part of the intracellular domain was ineffective. Lipid raft disruption prevented ALP-induced Fas/CD95 clustering, DISC formation, and apoptosis. ALP-induced apoptosis was Fas/CD95 ligand (FasL/CD95L) independent. ALP-induced recruitment of death receptors in lipid rafts potentiated MM cell killing by FasL/CD95L and TRAIL. These data uncover a novel lipid raft-mediated therapy in MM involving concentration of death receptors in membrane rafts, with Fas/CD95 playing a major role in ALP-mediated apoptosis.
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PMID:Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. 1700 75

Since a variety of cell intrinsic and extrinsic molecular abnormalities cooperatively promote tumor formation in multiple myeloma (MM), therapeutic approaches that concomitantly target more than one molecule are increasingly attractive. We herein demonstrate the anti-myeloma effect of a cephalotaxus alkaloid, homoharringtonine (HHT), an inhibitor of protein synthesis, through the induction of apoptosis. HHT significantly reduced Mcl-1, a crucial protein involved in myeloma cell survival, in all three myeloma cell lines examined, whereas certain BH3-only proteins, such as Bim, Bik, and Puma, remained unchanged following HHT treatment, and their expression levels depended on the cell type. HHT also reduced the levels of c-FLIP(L/S), activated caspase-8, and induced active truncated-Bid. Thus, HHT-induced apoptosis appears to be mediated via both intrinsic and extrinsic apoptosis pathways, and the resultant imbalance between BH3-only proteins and Mcl-1 may be pivotal for apoptosis by HHT. In addition, HHT treatment resulted in reduced levels of beta-catenin and XIAP proteins, which also contribute to disease progression and resistance to chemotherapy in MM. In combination, HHT enhanced the effects of melphalan, bortezomib, and ABT-737. These results suggest that HHT could constitute an attractive option for MM treatment though its ability to simultaneously target multiple tumor-promoting molecules.
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PMID:Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and beta-catenin. 1841 56

TP-110, a new proteasome inhibitor, has previously shown potent growth inhibition in various tumor cell lines. In this study, the mechanism of TP-110-induced apoptosis is investigated in a human multiple myeloma cell line. Treatment with TP-110 for 24 h in vitro induced apoptosis in multiple myeloma cell line RPMI8226. Although the expression of Bcl-2, Bcl-xL and Bax was not affected by the treatment of TP-110, cleavage of Bid and release of cytochrome c were enhanced. Interestingly, TP-110 reduced the intrinsic inhibitor of apoptosis proteins (IAPs), cIAP-1 and XIAP, that suppress executioner caspases. The reduction of IAPs was observed not only by TP-110, but also by another proteasome inhibitor, MG-132. These results indicate that proteasome inhibitors reduce the level of IAPs and that the apoptosis induced by TP-110 is correlated with the level of IAPs in leukemia cell lines. Additionally, a reduction of cIAP-1 and XIAP by TP-110 contributes to the sensitization of Fas-mediated apoptosis. Taken together, the alteration of the apoptosis regulatory proteins by a proteasome inhibitor induces apoptosis in tumor cells.
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PMID:TP-110, a new proteasome inhibitor, down-regulates IAPs in human multiple myeloma cells. 1941 35

We have found that resveratrol (trans-3,4',5-trihydroxystilbene) induced apoptosis in multiple myeloma (MM) and T-cell leukemia cells through coclustering of Fas/CD95 death receptor and lipid rafts, whereas normal lymphocytes were spared. Tumor necrosis factor-related apoptosis-inducing ligand receptors, Fas-associated death domain-containing protein (FADD), procaspase-8, procaspase-10, c-Jun amino-terminal kinase and Bid were also recruited into lipid rafts on resveratrol incubation with MM and T-cell leukemia cells. Raft disruption inhibited resveratrol-induced apoptosis. Bcl-XL overexpression prevented resveratrol-induced disruption of mitochondrial transmembrane potential (DeltaPsi(m)) and apoptosis. A FADD dominant-negative mutant, that blocked Fas/CD95 downstream signaling, precluded resveratrol-induced DeltaPsi(m) loss and apoptosis, indicating a sequence of Fas/CD95 signaling-->mitochondrion in the apoptotic response triggered by resveratrol. Cells deficient in Fas/CD95 did not undergo resveratrol-induced apoptosis. Pretreatment of MM cells with interferon-gamma upregulated Fas/CD95 and caspase-8, and potentiated resveratrol-induced apoptosis. Our data indicate that recruitment of Fas/CD95 death receptor and downstream signaling molecules into lipid rafts, followed by DeltaPsi(m) disruption, underlies the apoptotic action of resveratrol in MM and T-cell leukemic cells. Combination of resveratrol with perifosine or bortezomib potentiated the apoptotic response induced by each single drug. These results also highlight the role of recruitment of Fas/CD95 signaling in lipid rafts in antimyeloma and antileukemia chemotherapy.
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PMID:Involvement of mitochondria and recruitment of Fas/CD95 signaling in lipid rafts in resveratrol-mediated antimyeloma and antileukemia actions. 1956 42

Despite recent treatment advances, multiple myeloma (MM) remains incurable and patients develop a progressively relapsing disease with subsequent poor prognosis. Studies have shown FTY720 has activities against a number of hematological malignancies including MM, no reports about autophagy induced by FTY720 in MM. Therefore, we investigated the potential application of FTY720 on MM using U266 cell line. We observed that FTY720 could induce caspase-3 dependent apoptosis in a dose- and time-dependent manner in U266 cells. FTY720 caused apoptosis by down-regulating antiapoptotic proteins Mcl-1, bcl-2, survivin and cleavage of Bid. Interestingly, FTY720 induce autophagy which could promote the apoptosis in U266 cells. Furthermore, activation of reactive oxygen species (ROS) regulates FTY720 induced apoptosis and autophagy in U266 cells. The study implicated that FTY720 could be a good candidate for MM treatment.
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PMID:Autophagy induced by FTY720 promotes apoptosis in U266 cells. 2228 42

Bcl2 and IAP families are anti-apoptotic proteins deregulated in multiple myeloma (MM) cells. Pharmacological inhibition of each of these families has shown significant activity only in subgroups of MM patients. Here, we have examined a broad-spectrum Bcl2 family inhibitor Obatoclax (OBX) in combination with a Smac mimetic LCL161 in MM cell lines and patient cells. LCL161/OBX combination induced synergistic cytotoxicity and anti-proliferative effects on a broad range of human MM cell lines. The cytotoxicity was mediated through inhibition of the IAPs, activation of caspases and up regulation of the pro-apoptotic proteins Bid, Bim, Puma and Noxa by the drug combination. In addition, we observed that OBX caused ER stress and activated the Unfolded Protein Response (UPR) leading to drug resistance. LCL161, however inhibited spliced Xbp-1, a pro-survival factor. In addition, we observed that OBX increased GRP78 localization to the cell surface, which then induced PI3K dependent Akt activation and resistance to cell death. LCL161 was able to block OBX induced Akt activation contributing to synergistic cell death. Our results support clinical evaluation of this combination strategy in relapsed refractory MM patients.
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PMID:Smac mimetic LCL161 overcomes protective ER stress induced by obatoclax, synergistically causing cell death in multiple myeloma. 2749 45

Multiple myeloma (MM) remains an incurable disease in need of the development of novel therapeutic agents and drug combinations. ABT-199 is a specific Bcl-2 inhibitor in clinical trials for MM; however, its activity as a single agent was limited to myeloma patients with the t(11;14) translocation who acquire resistance due to co-expression of Mcl-1 and Bcl-xL. These limitations preclude its use in a broader patient population. We have recently found that a sphingosine kinase 2-specific inhibitor (ABC294640) induces apoptosis in primary human CD138+ cells and MM cell lines. ABC294640 is currently in phase I/II clinical trials for myeloma (clinicaltrials.gov: #NCT01410981). Interestingly, ABC294640 down-regulates c-Myc and Mcl-1, but does not have any effects on Bcl-2. We first evaluated the combinatorial anti-myeloma effect of ABC294640 and ABT-199 in vitro in 7 MM cell lines, all of which harbor no t(11;14) translocation. Combination index calculation demonstrated a synergistic anti-myeloma effect of the combination of ABC294640 and ABT-199. This synergistic anti-myeloma effect was maintained even in the presence of bone marrow (BM) stromal cells. The combination of ABC294640 and ABT-199 led to enhanced cleavage of PARP and caspase-3/9 and increased Annexin-V expression, consistent with the induction of apoptosis by the combination treatment. In addition, the combination of ABC294640 and ABT-199 resulted in the down-regulation of the anti-apoptotic proteins Mcl-1, Bcl-2, and Bcl-xL and the cleavage of Bax and Bid. The combination induced both the mitochondrial mediated- and caspase-mediated apoptosis pathways. Finally, the combination of ABC294640 and ABT-199 resulted in augmented anti-myeloma effect in vivo in a mouse xenograft model. These findings demonstrate that the co-administration of ABC294640 and ABT-199 exhibits synergistic anti-myeloma activity in vitro and in vivo, providing justification for a clinical study of this novel combination in patients with relapsed/refractory multiple myeloma.
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PMID:The combination of a sphingosine kinase 2 inhibitor (ABC294640) and a Bcl-2 inhibitor (ABT-199) displays synergistic anti-myeloma effects in myeloma cells without a t(11;14) translocation. 2976 3


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