UMLS:C0026764 - FACTA Search

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)

Although PS-341 (bortezomib) is a promising agent to improve multiple myeloma (MM) patient outcome, 65% of patients with relapsed and refractory disease do not respond. We have previously shown that heat shock protein (Hsp)27 is upregulated after PS-341 treatment, that overexpression of Hsp27 confers PS-341 resistance, and that inhibition of Hsp27 overcomes PS-341 resistance. Since Hsp27 is a downstream target of p38 mitogen-activated protein kinase (MAPK)/MAPK-mitogen-activated protein kinase-2 (MAPKAPK2), we hypothesized that inhibition of p38 MAPK activity could augment PS-341 cytotoxicity by downregulating Hsp27. Although p38 MAPK inhibitor SCIO-469 (Scios Inc, CA, USA) alone did not induce significant growth inhibition, it blocked baseline and PS-341-triggered phosphorylation of p38 MAPK as well as upregulation of Hsp27, associated with enhanced cytotoxicity in MM.1S cells. Importantly, SCIO-469 enhanced phosphorylation of c-Jun NH2-terminal kinase (JNK) and augmented cleavage of caspase-8 and poly(ADP)-ribose polymerase. Moreover, SCIO-469 downregulated PS-341-induced increases in G2/M-phase cells, associated with downregulation of p21Cip1 expression. Importantly, SCIO-469 treatment augmented cytotoxicity of PS-341 even against PS-341-resistant cell lines and patient MM cells. These studies therefore provide the framework for clinical trials of SCIO-469 to enhance sensitivity and overcome resistance to PS-341, thereby improving patient outcome in MM.
...
PMID:p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. 1548 Apr 25

Cyclopentenone prostaglandins are potent inhibitors of nuclear factor-kappa B (NF-kappa B), a transcription factor with a critical role in promoting inflammation and connected with multiple aspects of oncogenesis and cancer cell survival. In the present report, we investigated the role of NF-kappa B in the antineoplastic activity of the cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) in multiple myeloma (MM) and Burkitt lymphoma (BL) cells expressing constitutively active NF-kappa B. 15d-PGJ(2) was found to suppress constitutive NF-kappa B activity and potently induce apoptosis in both types of B-cell malignancies. 15d-PGJ(2)-induced apoptosis occurs through multiple caspase activation pathways involving caspase-8 and caspase-9, and is prevented by pretreatment with the pan-caspase inhibitor ZVAD (z-Val-Ala-Asp). NF-kappa B inhibition is accompanied by rapid down-regulation of NF-kappa B-dependent antiapoptotic gene products, including cellular inhibitor-of-apoptosis protein 1 (cIAP-1), cIAP-2, X-chromosome-linked inhibitor-of-apoptosis protein (XIAP), and FLICE-inhibitory protein (cFLIP). These effects were mimicked by the proteasome inhibitor MG-132, but not by the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist troglitazone, suggesting that 15d-PGJ(2)-induced apoptosis is independent of PPAR-gamma. Knockdown of the NF-kappa B p65-subunit by lentiviral-mediated shRNA interference also resulted in apoptosis induction in malignant B cells with constitutively active NF-kappa B. The results indicate that inhibition of NF-kappa B plays a major role in the proapoptotic activity of 15d-PGJ(2) in aggressive B-cell malignancies characterized by aberrant regulation of NF-kappa B.
...
PMID:15-Deoxy-delta 12,14-prostaglandin J2 induces apoptosis in human malignant B cells: an effect associated with inhibition of NF-kappa B activity and down-regulation of antiapoptotic proteins. 1549 50

Triptolide has been reported to be effective in the treatment of auto-immune diseases. This study investigates the cytotoxic function of triptolide on multiple myeloma (MM) cells. We found that triptolide inhibited the proliferation of both RPMI8226 and U266 cells in a dose-dependent manner (10-80 ng/mL). Triptolide induced apoptosis in MM cells through activation of the cystein protease caspase 8, 9 and 3, and subsequent cleavage of the DNA repair enzyme poly (ADP-ribose) polymerase. Apoptosis was confirmed with cell-cycle analysis and annexin V staining. Moreover, triptolide down-regulated nuclear factor (NF)-kappaB activity in MM cell lines. In addition, triptolide also induced chemosensitivity to doxorubicin and suppressed cell proliferation of fresh MM cells. Therefore, triptolide appears to be a potent inducer of apoptosis in myeloma cells, and might have some benefit in the treatment of myeloma patients.
...
PMID:Triptolide inhibits transcription factor NF-kappaB and induces apoptosis of multiple myeloma cells. 1554 81

Topoisomerase I inhibitors are effective anticancer therapies and have shown activity in hematologic malignancies. Here we show for the first time that SN38, the potent active metabolite of irinotecan, induces c-Jun NH(2)-terminal kinase activation, Fas up-regulation, and caspase 8-mediated apoptosis in multiple myeloma (MM) cells. Proteasomal degradation of nuclear topoisomerase I has been proposed as a resistance mechanism in solid malignancies. SN38-induced proteasomal degradation of topoisomerase I was observed during SN38-mediated cytotoxicity against MM.1S myeloma cell line but occurred after c-Jun NH(2)-terminal kinase activation, Fas up-regulation, and poly(ADP-ribose) polymerase cleavage and failed to protect cells from apoptosis. Differential toxicity was observed against MM cells versus bone marrow stromal cells, and SN38 inhibited adhesion-induced up-regulation of MM cell proliferation when MM cells adhere to bone marrow stromal cells. In addition, SN38 directly inhibited constitutive and inducible interleukin 6 and vascular endothelial growth factor secretion by bone marrow stromal cells. Synergy was observed when SN38 was used in combination with doxorubicin, bortezomib, as well as poly(ADP-ribose) polymerase inhibitor NU1025 and Fas-activator CH11. These findings have clinical significance, because identification of downstream apoptotic signaling after topoisomerase I inhibition will both elucidate mechanisms of resistance and optimize future combination chemotherapy against MM.
...
PMID:Proteasomal degradation of topoisomerase I is preceded by c-Jun NH2-terminal kinase activation, Fas up-regulation, and poly(ADP-ribose) polymerase cleavage in SN38-mediated cytotoxicity against multiple myeloma. 1557 86

NS-398, a selective inhibitor of cyclooxygenase 2 (COX-2), has been reported to inhibit growth and induce apoptosis in several cancer cell lines that overexpress COX-2. However it has not been extensively studied in multiple myeloma (MM). Here, we studied the effects of COX-2 inhibitors on MM cell lines and primary myeloma patient cells. We investigated the effects of NS-398 on proliferation and apoptosis in three myeloma cell lines (PCM6, U266 and RPMI8226) and isolated CD138-positive cells from MM patients. Furthermore, the combined effects of NS-398 plus dexamethasone (Dex) or thalidomide (Thal) were investigated. All myeloma cell lines express COX-2. NS-398 inhibited growth and induced apoptosis in PCM6, RPMI8226 and CD138-positive MM cells in a time- and dose-dependent manner. At low concentrations (10 microM), NS-398 primarily induced growth arrest without affecting cell viability, but at higher concentrations (over 25 microM), apoptosis was induced. During the process of apoptosis, the number of Fas-positive cells increased. Downstream signals of Fas, such as caspase 8, 3 and 9, were also activated. On the other hand, protein levels of the Bcl-2 family did not change, although mitochondrial transmembrane potential ((Delta)(psi)m) was decreased. Combined incubation with Dex or Thal enhanced NS-398-induced growth inhibition and apoptosis in RPMI8226 cells. The combined effect of Dex was more potent than that of Thal. Our findings suggests that COX-2 plays an important role in regulation of apoptosis in myeloma cells, and COX-2 inhibitors might serve as an effective tool for future chemoprevention and/or treatment of myeloma.
...
PMID:Selective cyclooxygenase 2 inhibitor NS-398 induces apoptosis in myeloma cells via a Bcl-2 independent pathway. 1562 34

Statins have been used successfully in the treatment of hypercholesteremia. Moreover, in vitro studies have shown that statins can trigger apoptosis in a variety of tumor cell lines. In the present study we analysed the effect of mevastatin -- a novel inhibitor of HMG-COA reductase, the rate-limiting enzyme of the mevalonate pathway -- on U266 human myeloma cells. Apoptosis induced by mevastatin was associated with increased caspase activity and depolarisation of mitochondrial membrane. Expression of BCL-2 mRNA and protein was down-regulated, with no change in BAX or BCLxL protein production. The mitochondrial program was supported by caspase-8 and cleaved BID activity. None of the antibodies neutralising death-ligand/death-receptor pathway -- TRAIL-R2Fc, anti-TNF-a, anti FASL (NOK-1) -- influenced the mevastatin-induced apoptosis. Mevastatin also stimulated shedding of syndecan-1 from the surface of myeloma cells.
...
PMID:[Mevastatin induced apoptosis in U266 human myeloma cell line]. 1565 79

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.
...
PMID:Molecular characterization of PS-341 (bortezomib) resistance: implications for overcoming resistance using lysophosphatidic acid acyltransferase (LPAAT)-beta inhibitors. 1573 76

Ras activation (by point mutation or binding of IL-6) is frequently observed in multiple myeloma (MM). As farnesylation of Ras protein by farnesyltransferase is a critical step for Ras functional activity, farnesyltransferase inhibitors (FTI) have emerged as potential anti-cancer agents. Manumycin, a natural FTI, prevents proliferation and induces apoptosis of myeloma cells refractory to Fasand drug-induced cell death. Fas pathway analysis showed that Fas-resistant apoptosis of Fas-positive myeloma cells parallels FLIP (FLICE/caspase-8-inhibitory protein) expression. Treatment of fresh purified myeloma cells, myeloma cell clone-2 and U266 cell line with manumycin induced down-regulation of FLIP expression with concomitant expression of Apo 2.7 antigen, the marker of early apoptosis. Down-regulation of FLIP mRNA levels in drug-treated cells was associated to suppression of the transcription factor NF-kappaB that plays a central role in chemoresistance, survival and proliferation of myeloma cells. Further analysis showed that manumycin-induced apoptosis involved caspases activation and was prevented by the addition of caspases specific inhibitors. Finally, pretreatment of Fas-resistant/FLIP-positive cells with manumycin sensitised them to Fas-triggered apoptosis. Overall results indicate that manumycin-induced apoptosis involves Fas pathway. FTIs may thus be proposed as a promising class of anti-cancer agents which can boost the cytotoxic effect of conventional drugs by overcoming NF-kappaB activation and Fas-resistant apoptosis.
...
PMID:Blockade of the Ras pathway by manumycin, a farnesyltransferase inhibitor, overcomes the resistance of myeloma plasma cells to Fas-induced apoptosis. 1575 Jul 64

In this study we report that R-etodolac (SDX-101), at clinically relevant concentrations, induces potent cytotoxicity in drug-sensitive multiple myeloma (MM) cell lines, as well as in dexamethasone (MM.1R)-, doxorubicin (Dox40/RPMI8226)-, and bortezomib (DHL4)-resistant cell lines. Immunoblot analysis demonstrates that R-etodolac induces apoptosis characterized by caspase-8, -9, and -3 and PARP (poly-ADP [adenosine diphosphate]-ribose polymerase) cleavage and down-regulation of cyclin D1 expression. Subcytotoxic doses of R-etodolac up-regulate myeloid cell leukemia-1 proapoptotic variant (Mcl-1S), while enhancing dexamethasone (Dex)-induced caspase activation and apoptosis. The combination of R-etodolac with Dex results in a highly synergistic cytotoxic effect. R-etodolac also induces apoptosis against primary cells isolated from patients with MM refractory to chemotherapy. Although interleukin 6 (IL-6) and insulin-like growth factor-1 (IGF-1) abrogate Dex-induced MM cell cytotoxicity, neither IL-6 nor IGF-1 protects against R-etodolac-induced cytotoxicity in MM cells. R-etodolac also inhibits viability of MM cells adherent to bone marrow stromal cells (BMSCs), thereby overcoming a mechanism of drug resistance commonly observed with other conventional chemotherapeutic agents. Our data, therefore, indicate that R-etodolac circumvents drug resistance in MM cells at clinically relevant concentrations, targets Mcl-1, and can be synergistically combined with Dex.
...
PMID:SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma. 1580 27

Multiple myeloma (MM) is an as-yet incurable B-cell malignancy. Increased survival in vitro is a hallmark of MM cells, implying that a therapeutic potential may lie in circumventing antiapoptotic signals. We have previously reported that interferons (IFNs) sensitize MM cells to Fas/CD95-mediated apoptosis. In the present study, we explore the mechanism underlying this effect. In a wide screening of apoptosis-related genes, Apo2L/TRAIL (tumor necrosis factor [TNF]-related apoptosis inducing ligand) and Fas were identified as IFN targets. Sensitization to Fas-mediated apoptosis by IFNs was not affected by blocking Apo2L/TRAIL, suggesting that Apo2L/TRAIL is not a key mediator in this process. In contrast, we found that an elevated Fas expression was functionally linked to increased susceptibility to Fas-mediated apoptosis. This was further supported by the finding that IFN treatment enhanced Fas-mediated caspase-8 activation, one of the earliest signaling events downstream receptor activation. In addition, IFN treatment attenuated the interleukin 6 (IL-6)-dependent activation of signal transducer and activator of transcription 3 (Stat3), interfering with a known survival pathway in MM that has previously been linked with resistance to Fas-mediated apoptosis. Taken together, our results show that IFN-induced up-regulation of Fas sensitizes MM cells to Fas-mediated apoptosis and suggest that attenuation of Stat3 activation may be a potentially important event in this process.
...
PMID:Ectopic and IFN-induced expression of Fas overcomes resistance to Fas-mediated apoptosis in multiple myeloma cells. 1586 Jun 71

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>