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)

Despite the expression of Fas, some clones of myeloma cells are resistant to Fas-mediated apoptosis. To define a cellular factor involved in the resistance, we performed a comparative study using two clones of myeloma cells, RPM18226 and U266. These cells were reported to express cell surface Fas at similar levels, but only RPM18226 cells lost their viability upon anti-Fas treatment. The resistance of U266 cells to anti-Fas did not appear to reflect dysregulation of Bcl-2, Bcl-X(L), and Bax, because these proteins were expressed in both RPM18226 and U266 cells to similar levels. Moreover, levels of those proteins were not significantly altered by treating RPM18226 cells with IL-6, a cytokine which suppresses the Fas-mediated death of RPM18226 cells. Interestingly, mRNA levels of FLIP(L), an endogenous inhibitor of Fas signaling, were constitutively elevated in U266 cells. Consistent with this observation, U266 cells expressed both FLIPL protein and its truncated 43 kDa product which is seen in FLIP(L)-overexpressing cells. The truncated form of FLIP(L) protein was not detected in RPM18226. Moreover, the levels of truncated FLIP(L) in U266 cells were considerably higher than those of pro-FLIP(L) in RPM18226. The overall data indicate that FLIPL is constitutively hyperexpressed in U266 cells. However, IL-6 failed to enhance the protein levels of FLIP molecules in either of the tested cells. It appears, therefore, that FLIP(L) plays a role in the intrinsic resistance of U266 cells to the apoptotic action of Fas, but is not involved in the protective action of IL-6.
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PMID:FLIP is constitutively hyperexpressed in Fas-resistant U266 myeloma cells, but is not induced by IL-6 in Fas-sensitive RPM18226 cells. 1110 Nov 47

We have recently reported that Mcl-1, an anti-apoptotic member of the Bcl-2 family, is upregulated by interleukin (IL)-6 in human myeloma cells through the janus kinase/signal transducers and activators of transduction (JAK/STAT) pathway. In the current study, we have explored the effects of interferon (IFN)-alpha, a cytokine which has been shown to increase myeloma cell survival. Our results demonstrate that IFN-alpha potently upregulates Mcl-1 on both myeloma cell lines and purified native myeloma cells. Of note, this upregulation is not due to an induction of an IL-6 autocrine loop. Furthermore, we showed that IL-6 and IFN-alpha had no additive effect on Mcl-1 upregulation, suggesting that both cytokines act through a common mechanism. Finally, the analysis of signalling transduction pathways strongly suggests that Mcl-1 upregulation induced by IFN-alpha depends on STAT3 activation. Altogether, our data show that IFN-alpha has an IL-6-like effect on human myeloma cells and suggest that it could be deleterious in some patients.
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PMID:Interferon alpha extends the survival of human myeloma cells through an upregulation of the Mcl-1 anti-apoptotic molecule. 1116 29

As survival regulation is a key process in multiple myeloma biology, we have studied the Bcl-2 family proteins that can be regulated by three myeloma cell survival factors: interleukin-6 (IL-6), interferon-alpha (IFN-alpha) and insulin-like growth factor (IGF-1). Eleven myeloma cell lines, whose survival and proliferation are dependent on addition of IL-6, variably expressed 10 anti-apoptotic or pro-apoptotic proteins of the Bcl-2-family. When myeloma cells from four cell lines were IL-6 starved and activated with IL-6 or IFN-alpha, we observed that only Mcl-1 expression was up-regulated with myeloma cell survival induction. Nor was obvious regulation of these 10 pro-apoptotic or anti-apoptotic proteins found with IGF-1, another potent myeloma cell survival factor. Our results indicate that the myeloma cell survival activity of IL-6 linked to Bcl-xL regulation cannot be generalized and emphasize that Mcl-1 is the main target of IL-6 and IFN-alpha stimulation. However, other changes in the activity of the Bcl-2 protein family or other apoptosis regulators must be identified to elucidate the IGF-1 action mechanism. Cell Death and Differentiation (2000) 7, 1244 - 1252.
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PMID:Regulation of Bcl-2-family proteins in myeloma cells by three myeloma survival factors: interleukin-6, interferon-alpha and insulin-like growth factor 1. 1117 62

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by slow-growing plasma cells in the bone marrow (BM). Patients with MM typically respond to initial chemotherapies; however, essentially all progress to a chemoresistant state. Factors that contribute to the chemorefractory phenotype include modulation of free radical scavenging, increased expression of drug efflux pumps, and changes in gene expression that allow escape from apoptotic signaling. Recent data indicate that arsenic trioxide (As(2)O(3)) induces remission of refractory acute promyelocytic leukemia and apoptosis of cell lines overexpressing Bcl-2 family members; therefore, it was hypothesized that chemorefractory MM cells would be sensitive to As(2)O(3). As(2)O(3) induced apoptosis in 4 human MM cell lines: 8226/S, 8226/Dox40, U266, and U266/Bcl-x(L). The addition of interleukin-6 had no effect on cell death. Glutathione (GSH) has been implicated as an inhibitor of As(2)O(3)-induced cell death either through conjugating As(2)O(3) or by sequestering reactive oxygen induced by As(2)O(3). Consistent with this possibility, increasing GSH levels with N-acetylcysteine attenuated As(2)O(3) cytotoxicity. Decreases in GSH have been associated with ascorbic acid (AA) metabolism. Clinically relevant doses of AA decreased GSH levels and potentiated As(2)O(3)-mediated cell death of all 4 MM cell lines. Similar results were obtained in freshly isolated human MM cells. In contrast, normal BM cells displayed little sensitivity to As(2)O(3) alone or in combination with AA. Together, these data suggest that As(2)O(3) and AA may be effective antineoplastic agents in refractory MM and that AA might be a useful adjuvant in GSH-sensitive therapies. (Blood. 2001;98:805-813)
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PMID:Ascorbic acid enhances arsenic trioxide-induced cytotoxicity in multiple myeloma cells. 1146 82

Genasense (formerly known as G-3139), an antisense oligonucleotide specific for Bcl-2, is under development by Genta as an iv drip infusion for the potential treatment of various cancers including melanoma, prostate, breast and colon cancer [3083751. It is in phase III trials for malignant melanoma, for which it has been awarded Fast Track status 1359044]. Genasense received Orphan Drug status in August 2000 [3782331. In September 2000, the company announced that pivotal phase III trials in multiple melanoma, chronic lymphocytic leukemia (CLL) and acute myelocytic leukemia (AML) would be underway by 2001 [382783]. By January 2001, trials in AML and CLL had been initiated 1396512]. As of February 2001, Genta was planning the initiation of two additional, registration quality trials. Pending positive results from these trials, launch of Genasense is anticipated in 2002 13984111. A phase III trial in patients with advanced multiple myeloma at 65 centers in the US, Canada and Great Britain began in February 2001. The trial will examine whether the addition of Genasense can improve response rates, response duration and quality of life compared with dexamethasone therapy alone 13989081. Genta Inc has been issued a patent (US-05831066) for Genasense 1283005]. The patent provides protection to Genta for the composition of Genasense and its analogs. Furthermore, Genta Inc has also been issued two new patents that cover a series of compounds containing new backbone constructions that enhance the antisense affinity of the drug to the target pre-RNA, while the other patent covers the methods for preparation of antisense oligonucleotides containing the new backbone structures 12896851. Genta has already licensed the rights for the use of Bd-2 as a target for antisense- and gene therapy-based treatments from The University of Pennsylvania. The licensing agreements with Chugai Pharmaceutical Co for worldwide marketing and profit sharing places Genta in a favorable position. In January 2001, Needham & Co expected Genasense to have a potential market of 47,700 malignant melanoma patients in the US. The analysts also expected potential patient market sizes of 50,000 (CLL), 21,000 (AML), 136,000 (non-small cell lung cancer; NSLCC) and 180,000 (prostate cancer) in the US. In addition, the analysts predicted that Genasense would be approved for melanoma in the second quarter of 2002, with approvals to follow for CLL (third quarter of 2002), AML (third quarter of 2002) and myeloma (fourth quarter of 2002) 1399251].
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PMID:Genasense (Genta Inc). 1156 20

It has been reported that interferons (IFNs) may have antitumor activity in multiple myeloma (MM). The mechanism for their effect on MM, however, remains elusive. This study shows that IFN-alpha and -beta, but not -gamma, induce apoptosis characterized by Annexin V positivity, nuclear fragmentation and condensation, and loss of clonogenicity in 3 MM cell lines (U266, RPMI-8266, and NCI-H929), and in plasma cells from 10 patients with MM. Apo2 ligand (Apo2L, also TRAIL) induction was one of the earliest events following IFN administration in U266 cells. Treatment of these cells with TRAIL, but not with Fas agonistic antibodies, induces apoptosis. Cell death induced by IFNs and Apo2L in U266 cells was partially blocked by a dominant-negative Apo2L receptor, DR5, demonstrating the functional significance of Apo2L induction. This study shows that IFNs activate caspases and the mitochondrial-dependent apoptotic pathway, possibly mediated by Apo2L production. Thus, IFN-alpha and -beta induce cytochrome c release from mitochondria starting at 12 hours, with an amplified release seen at 48 hours. Moreover, Bid cleavage precedes the initial cytochrome c release, whereas the late, amplified cytochrome c release coincides with changes in levels of Bcl-2, Bcl-X(L), and reduction of mitochondrial membrane potential. These results link the Apo2L induction and modulation of Bcl-2 family proteins to mitochondrial dysfunction. Furthermore, IFNs and Apo2L induce cell death of CD38(+)/CD45(-/dim) plasma cells, without significant effect on nonplasma blood cells, in a caspase and Bcl-2 cleavage-dependent manner. These results warrant further clinical studies with IFNs and Apo2L in MM.
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PMID:Apo2L/TRAIL and Bcl-2-related proteins regulate type I interferon-induced apoptosis in multiple myeloma. 1156 6

The newly discovered member of the tumor necrosis factor superfamily, Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), has been identified as an apoptosis-inducing agent in sensitive tumor cells but not in the majority of normal cells, and hence it is of potential therapeutic application. However, many tumor cells are resistant to Apo2L/TRAIL-mediated apoptosis. Various chemotherapeutic drugs have been shown to sensitize tumor cells to members of the tumor necrosis factor family. However, it is not clear whether sensitization by drugs and sensitivity to drugs are related or distinct events. This study examined whether an Adriamycin-resistant multiple myeloma (MM) cell line (8226/Dox40) can be sensitized by Adriamycin (ADR) to Apo2L/TRAIL-mediated apoptosis. Treatment with the combination of Apo2L/TRAIL and subtoxic concentrations of ADR resulted in synergistic cytotoxicity and apoptosis for both the parental 8226/S and the 8226/Dox40 tumor cells. Adriamycin treatment modestly up-regulated Apo2L/TRAIL-R2 (DR5) and had no effect on the expression of Fas-associated death domain, c-FLIP, Bcl-2, Bcl(xL), Bax, and IAP family members (cIAP-1, cIAP-2, XIAP, and survivin). The protein levels of pro-caspase-8 and pro-caspase-3 were not affected by ADR, whereas pro-caspase-9 and Apaf-1 were up-regulated. Combination treatment with Apo2L/TRAIL and ADR resulted in significant mitochondrial membrane depolarization and activation of caspase-9 and caspase-3 and apoptosis. Because ADR is shown to sensitize ADR-resistant tumor cells to Apo2L/TRAIL, these findings reveal that ADR can still signal ADR-resistant tumor cells, resulting in the modification of the Apo2L/TRAIL-mediated signaling pathway and apoptosis. These in vitro findings suggest the potential application of combination therapy of Apo2L/TRAIL and subtoxic concentrations of sensitizing chemotherapeutic drugs in the clinical treatment of drug-resistant/Apo2L/TRAIL-resistant multiple myeloma.
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PMID:Adriamycin sensitizes the adriamycin-resistant 8226/Dox40 human multiple myeloma cells to Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-mediated (TRAIL) apoptosis. 1175 78

Although myeloma shows responsiveness in intensive chemotherapy, overall survival remains less than 40% at 2 years. Since myeloma appears to be dependent on cytokines, such as IL-6, we hypothesized that targeting signal transduction molecules could effectively treat myeloma. Two myeloma cell lines U266 and RPMI-8226 and CD38+ myeloma cells were studied by immune complex kinase assay or anti-phosphotyrosine blot for evidence of constitutive activation of tyrosine kinases. Growth arrest and apoptosis were evaluated in these two cell lines following their treatment with specific kinase inhibitors. We found that a variety of Src and Janus kinases were present and constitutively active in U266 and RPMI-8226 cells. Inhibitors of both Src and Janus kinases were inferior to the cyclin-dependent kinase inhibitor, flavopiridol, in inducing both growth arrest with GI50 of 100 nM and apoptosis in both cell lines and CD38+ myeloma cells. Although, flavopiridol did not affect cyclin D1 and cyclin A levels, it inhibited Mcl-1 and Bcl-2 protein levels and cyclin-dependent kinase 2 activity. Flavopiridol is a well-tolerated drug, currently in phase I-II trials for a variety of tumors. A clinical trial using flavopiridol should be performed in patients with myeloma. Its mechanism of action may involve targets other than the cyclin-dependent kinases.
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PMID:Growth inhibition and apoptosis of myeloma cells by the CDK inhibitor flavopiridol. 1179 16

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow caused primarily by failure of normal homeostatic mechanisms to prevent the expansion of postgerminal center plasma cells. We have examined the molecular mechanisms that promote the survival of MM cells and have identified a key role for myeloid cell factor-1 (Mcl-1), an antiapoptotic member of the Bcl-2 family. These experiments were initiated by the observation that MM cells were exquisitely sensitive to culture in the presence of actinomycin D: caspase activation occurred within 3 hours of treatment and cells were not protected by interleukin-6, the main MM cell growth and survival factor. Actinomycin D-induced apoptosis was blocked by proteasome inhibitors, suggesting that a labile protein was required for MM cell survival. Further analysis demonstrated that Mcl-1 was likely to be the labile factor governing MM cell survival. Mcl-1 protein levels decreased rapidly after culture in the presence of actinomycin D in concordance with effector caspase activation, but addition of proteasome inhibitors reversed the loss of Mcl-1 and maintained cell viability. The levels of other antiapoptotic proteins, including Bcl-2 and members of the inhibitors-of-apoptosis family, were unaffected by these interventions. Furthermore, Mcl-1 antisense oligonucleotides caused a rapid down-regulation of Mcl-1 protein levels and the coincident induction of apoptosis, whereas overexpression of Mcl-1 delayed actinomycin D-induced apoptosis with kinetics that correlated with expression levels of Mcl-1. These data indicate that Mcl-1 expression is required for the survival of MM cells and may represent an important target for future therapeutics.
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PMID:Myeloid cell factor-1 is a critical survival factor for multiple myeloma. 1187 56

Recently, it was disclosed that all-trans retinoic acid (ATRA) inhibits myeloma cell growth by downregulating the interleukin 6 (IL-6)/IL-6 receptor (IL-6R) auto/paracrine loop, and upregulating p21/Cip1 cyclin-dependent kinase inhibitor (CDK-I), thereby inducing apoptosis with a decrease in Bcl-2 protein expression. To elucidate and generalize the effects of ATRA on the proliferation and cellular biology of myeloma cells, 12 human myeloma cell lines established in our laboratory were utilized. Two out of the 12 lines showed enhanced growth on supplementation of ATRA and were characterized by IL-10 production, downregulation of membrane Fas and reduced upregulation of p21/Cip1 CDK-I message. These characteristics may prove important for the clinical use of ATRA and should be considered before starting ATRA therapy for myeloma.
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PMID:Interleukin 10 abolishes the growth inhibitory effects of all-trans retinoic acid on human myeloma cells. 1188 82


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