UMLS:C0026764 - FACTA Search

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Query: UMLS:C0026764 (multiple myeloma)
36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to investigate the mechanism of apoptosis in human multiple myeloma cell line, U266, caused by 2-aminophenoxazine-3-one (Phx-3). Flow-cytometrical and morphological analyses showed that Phx-3 increased the population of annexin V-positive cells including early stage apoptotic cells and late stage apoptotic cells and induced DNA fragmentation or apoptotic body formation in U266 cells, indicating that Phx-3 induced the apoptosis of U266 cells. Activity of caspase-3 was extensively increased in U266 cells treated with Phx-3 time-dependently within 24 h, but this Phx-3-stimulated activity of the enzyme in the cells was completely cancelled by the addition of N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), a pan-caspase inhibitor. The addition of z-VAD-fmk almost blocked the apoptotic effect of Phx-3 against U266 cells, indicating that Phx-3-induced apoptosis of U266 cells was dependent on a caspase signaling pathway. Moreover, the apoptosis of U266 cells occurred after the induction of cell cycle arrest of the cells in the S and G(2)/M phase, the loss of mitochondrial membrane potential, and activation of caspase-3 reached maximum, which were caused by Phx-3 within 24 h. These results support the views that the apoptosis of U266 cells caused by Phx-3 may be preceded by the cell cycle arrest, depolarization of mitochondria and activation of caspase-3. These results support the view that Phx-3 may be utilized in future as chemotherapeutic agent against multiple myeloma which is extremely refractory to chemotherapy.
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PMID:Apoptosis induction preceded by mitochondrial depolarization in multiple myeloma cell line U266 by 2-aminophenoxazine-3-one. 1817 43

To ascertain the exact anti-myeloma mechanism of thalidomide in vivo, we performed structural development studies of thalidomide, and obtained various analogues with specific molecular properties. Among these derivatives, we found that a new thalidomide analogue, 2-(2,6-diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione (5HPP-33) had the most potent anti-myeloma effect and tubulin-polymerization-inhibiting activity. 5HPP-33 directly inhibited the growth and survival of various myeloma cell lines (RPMI8226, U266, and IM9) in a dose-dependent manner with IC50 of 1-10 microM. In contrast, thalidomide itself did not inhibit cellular growth of RPMI8226 cells. Cultivation with 10 microM 5HPP-33 induced G2/M phase cell cycle arrest, followed by apoptosis of myeloma cells. Treatment with 5HPP-33 induced caspase-3 activity and PARP cleavage. A tubulin polymerization assay using microtubule protein from porcine brain revealed that 5HPP-33 showed potent tubulin-polymerization-inhibiting activity with IC50 of 8.1 microM, comparable to that of the known tubulin-polymerization inhibitor, rhizoxin. Moreover, its activity was more potent than that of a known thalidomide metabolite, 5-hydroxythalidomide. Notably, the structural requirement for its activity was critical, as other analogues and derivatives of 5HPP-33 showed only slight tubulin-polymerization-inhibiting activity. Our data suggest that 5HPP-33 is a promising candidates for a therapeutic agent of multiple myeloma. In addition, these results suggest that the tubulin-polymerization inhibiting activity of thalidomide might be a possible mechanism for inducing the apoptosis of myeloma cells by thalidomide.
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PMID:Novel tubulin-polymerization inhibitor derived from thalidomide directly induces apoptosis in human multiple myeloma cells: possible anti-myeloma mechanism of thalidomide. 1820 82

Aplidin is an antitumour drug, currently undergoing phase II evaluation in different haematological and solid tumours. In this study, we analysed the antimyeloma effects of Aplidin in the syngeneic 5T33MM model, which is representable for the human disease. In vitro, Aplidin inhibited 5T33MMvv DNA synthesis with an IC(50) of 3.87 nM. On cell-cycle progression, the drug induced an arrest in transition from G0/G1 to S phase, while Western blot showed a decreased cyclin D1 and CDK4 expression. Furthermore, Aplidin induced apoptosis by lowering the mitochondrial membrane potential, by inducing cytochrome c release and by activating caspase-9 and caspase-3. For the in vivo experiment, 5T33MM-injected C57Bl/KaLwRij mice were intraperitoneally treated with vehicle or Aplidin (90 microg kg(-1) daily). Chronic treatment with Aplidin was well tolerated and reduced serum paraprotein concentration by 42% (P<0.001), while BM invasion with myeloma cells was decreased by 35% (P<0.001). Aplidin also reduced the myeloma-associated angiogenesis to basal values. This antiangiogenic effect was confirmed in vitro and explained by inhibition of endothelial cell proliferation and vessel formation. These data indicate that Aplidin is well tolerated in vivo and its antitumour and antiangiogenic effects support the use of the drug in multiple myeloma.
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PMID:Antitumour and antiangiogenic effects of Aplidin in the 5TMM syngeneic models of multiple myeloma. 1852 Oct 88

Multiple myeloma is an incurable B-cell malignancy requiring new therapeutic strategies in clinical settings. Interleukin (IL)-6 signaling pathways play a critical role in the pathogenesis of multiple myeloma. The traditional Chinese medicine cantharidin (CTD) has been shown to inhibit cellular proliferation and induce apoptosis of various cancer cells. The aim of this study was to investigate the possibility of CTD as a novel therapeutic agent for the patients with multiple myeloma. We investigated the in vitro effects of CTD for its antimyeloma activity, and further examined the molecular mechanisms of CTD-induced apoptosis. CTD inhibited the cellular growth of human myeloma cell lines as well as freshly isolated myeloma cells in patients. Cultivation with CTD induced apoptosis of myeloma cells in a cell-cycle-independent manner. Treatment with CTD induced caspase-3, -8, and -9 activities, and it was completely blocked by each caspase inhibitor. We further examined the effect of CTD on the IL-6 signaling pathway in myeloma cells, and found that CTD inhibited phosphorylation of STAT3 at tyrosine 705 residue as early as 1 h after treatment and down-regulated the expression of the antiapoptotic bcl-xL protein. STAT3 directly bound and activated the transcription of bcl-xL gene promoter, resulting in the induction of the expression of bcl-xL in myeloma cells. The essential role of STAT3 in CTD effects was confirmed by transfection with the constitutively active and dominant negative form of STAT3 in U266 cells. In conclusion, we have demonstrated that CTD is a promising candidate to be a new therapeutic agent in signal transduction therapy.
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PMID:Cantharidin induces apoptosis of human multiple myeloma cells via inhibition of the JAK/STAT pathway. 1854 87

Histone deacetylase inhibitors have emerged as promising anticancer drugs. Using an unbiased ultrahigh throughput screening system, a novel mercaptoketone-based histone deacetylase inhibitor series was identified that was optimized to the lead compound, KD5170. KD5170 inhibited the proliferation of myeloma cell lines and the viability of CD138(+) primary myeloma cells by induction of apoptosis, accompanied by an increase of acetylation of histones and activation of caspase-3, caspase-8, and caspase-9. Treatment with KD5170 caused a loss of mitochondrial membrane potential resulting in release of apoptogenic factors such as cytochrome c, Smac, and apoptosis-inducing factor. Furthermore, KD5170 induced oxidative stress and oxidative DNA damage in myeloma cells as evidenced by the up-regulation of heme oxygenase-1 and H2A.X phosphorylation. Combination of KD5170 with proteasome inhibitor bortezomib or tumor necrosis factor-related apoptosis-inducing ligand synergistically enhanced the antimyeloma activity. We further found that resistance of myeloma cells to KD5170 was associated with activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway under treatment with KD5170. Pretreatment with the mitogen-activated protein kinase inhibitor U0126 restored sensitivity to KD5170, suggesting that the combination of KD5170 with U0126 could overcome drug resistance. Growth of myeloma tumor xenografts in KD5170-treated nude mice was significantly inhibited and survival was prolonged. Histone acetylation was increased in spleen and tumor tissues of animals treated with KD5170. Our data indicate that KD5170 has potent antimyeloma activity in vitro and in vivo, which is mediated by DNA damage and mitochondrial signaling and subsequent induction of apoptosis.
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PMID:KD5170, a novel mercaptoketone-based histone deacetylase inhibitor, exerts antimyeloma effects by DNA damage and mitochondrial signaling. 1856 20

To explore the apoptotic effect of simvastatin on K562 cells through endoplasmic reticulum stress, morphological change of apoptotic cells was observed by Hoechst33258 fluorescent staining under fluorescent microscope. Apoptosis rate of cells was determined with annexinV-FITC/PI double staining by flow cytometry; Intracellular calcium concentration ([Ca2+]i) was measured by laser scanning confocal microscope (LSCM); The expression levels of glucose regulated protein 78 (GRP78) and calpain gene mRNA were determined by RT-PCR; The expression levels of caspase-3, -6, -7, -9, -12, calpain and GRP78 proteins were evaluated by Western blotting. In this study, K562 cells treated with simvastatin for 72 h exhibited typical morphological change of apoptosis cells. After 72 h exposed to 10, 20, 30 micromol x L(-1) simvastatin, the apoptotic rates of K562 cells were 12.41%, 19.08% and 23.41%, respectively. Simvastatin induced the increase of [Ca2+]i in K562 cells, fluorescent intensities were 43, 54, and 64, respectively. The expression levels of GRP78 and calpain gene mRNA were up-regulated. The cleavage and activation of caspase-3, -6, -7, -9, -12 and upregulation of GRP78 expression were determined by Western blotting. These findings suggest that endoplasmic reticulum is an important pathway of apoptosis in cells and participates simvastatin-induced apoptosis in K562 cells. It is implied that simvastatin may be suitable for clinical usage in the treatment of myeloma patients.
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PMID:[Simvastatin-induced apoptosis of K562 cells is mediated by endoplasmic reticulum stress]. 1866 98

Cepharanthine (CEP), a biscoclaurine alkaloid extracted from Stephania Cepharantha Hayata, has been used in Japan for treating patients with radiation-induced leucopenia or thrombocytopenia. We treated a patient with multiple myeloma (MM), who was not responding to preceding chemotherapy, who coincidently received therapy with CEP due to thrombocytopenia. Since the case showed a marked reduction of tumor load, direct anti-tumor effects of CEP to myeloma cells were investigated in vitro. Anti-tumor effects were observed in all myeloma cell lines tested, including a line resistant to melphalan. Exposure to CEP of a myeloma cell line induced the production of reactive oxygen species, activated the caspase-3 pathway and eventually induced apoptosis. Pre-exposure of cells to a pan-caspase inhibitor, Z-VAD-FMK, or a free radical scavenger, Tiron, effectively blocked CEP-induced apoptosis. Interestingly, CEP also inhibited cell growth of myeloma cells by inducing CDK inhibitors. These data show, for the first time, that CEP has anti-myeloma effects by the activation of apoptotic pathways and blocking cell cycle progression via CDK inhibitors. Although analysis of these two pathways should be clarified further, the use of CEP may be considered as a potential therapeutic agent for a subset of MM.
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PMID:Induction of cell cycle arrest and apoptosis in myeloma cells by cepharanthine, a biscoclaurine alkaloid. 1881 95

Velcade (also known as PS-341 or Bortezomib) is a highly selective and reversible inhibitor of the 26S proteasome and is approved for the treatment of patients with advanced multiple myeloma. Here we investigated the anti-proliferative effect of Velcade on 4T1 breast cancer and B16F10 melanoma cells and evaluated the mechanism of action. It was found that two cell lines are differentially sensitive to proteasome inhibitor Velcade. The IC50 concentrations for B16F10 and 4T1 were 2.5 nM and 71 nM, respectively, indicating that B16F10 cells are more sensitive to proteasomal inhibition. Velcade was equally potent in inhibiting the chymotrypsin-like activity of the proteasome in both cell lines. It was determined that B16F10 cells proliferate more rapidly than 4T1 cells; doubling time (Td) =14.2 h versus Td =22.9 h, suggesting that a rapid proliferation rate may be an important factor in cellular resistance towards proteasomal inhibition. We observed for the first time that p53 and p21 proteins were increased in B16F10 cells but not in 4T1 following Velcade-treatment, demonstrating that p53 and p21 may enhance Velcade sensitivity. Furthermore, it was observed that caspase-3 proenzyme was reduced by approximately 20% in B16F10 melanoma cells, but not in 4T1 cells in response to 26S proteasomal inhibition by Velcade. Altogether, we concluded that p53 protein plays a central role in higher sensitivity of B16F10 cells to Velcade by inducing the accumulation of p21, a cell cycle inhibitor, as well as by stimulating the mitochondrial pathway of apoptosis through caspase-3 activation.
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PMID:Differential sensitivity of breast cancer and melanoma cells to proteasome inhibitor Velcade. 1902 Jul 81

The proteasome inhibitor bortezomib is currently an important drug for treatment of relapsed and refractory multiple myeloma (MM) and for elderly patients. However, cells from some patients show resistance to bortezomib. We have evaluated the possibility of improving bortezomib therapy with Apo2L/TRAIL, a death ligand that induces apoptosis in MM but not in normal cells. Results indicate that cotreatment with low doses of bortezomib significantly increased apoptosis of MM cells showing partial sensitivity to Apo2L/TRAIL. Bortezomib treatment did not significantly alter plasma membrane amount of DR4 and DR5 but increased Apo2L/TRAIL-induced caspase-8 and caspase-3 activation. Apo2L/TRAIL reverted bortezomib-induced up-regulation of beta-catenin, Mcl-1 and FLIP, associated with the enhanced cytotoxicity of combined treatment. More important, some cell lines displaying resistance to bortezomib were sensitive to Apo2L/TRAIL-induced apoptosis. A cell line made resistant by continuous culture of RPMI 8226 cells in the presence of bortezomib (8226/7B) was highly sensitive to Apo2L/TRAIL-induced apoptosis. Moreover, RPMI 8226 cells overexpressing Mcl-1 (8226/Mcl-1) or Bcl-x(L) (8226/Bcl-x(L)) also showed enhanced resistance to bortezomib, but co-treatment with Apo2L/TRAIL reverted this resistance. These results indicate that Apo2L/TRAIL can cooperate with bortezomib to induce apoptosis in myeloma cells and can be an useful adjunct for MM therapy.
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PMID:Cooperation between Apo2L/TRAIL and bortezomib in multiple myeloma apoptosis. 1910 Jul 20

Iron chelators have been reported to induce apoptosis and cell cycle arrest in cancer cells. Recent studies suggest broad and selective antitumor activity of the new iron chelator, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT; Whitnall et al., Proc Natl Acad Sci USA 2006;103:14901-14906). However, little is known concerning its effects on hematological malignancies. Using acute leukemia cells, the effect of Dp44mT on apoptosis, cell cycle, caspase-3 activation, and mitochondrial trans-membrane potential has been examined by flow cytometry. Dp44mT acted to induce a G(1)/S arrest in NB4 promyelocytic leukemia cells at low concentrations (0.5-2.5 microM), being far more effective than the clinically used chelator, desferrioxamine (DFO). Moreover, Dp44mT induced apoptosis of NB4 cells in a dose- and time-dependent manner with markedly less effect on nonproliferating cells. The apoptosis-inducing activity of Dp44mT was significantly more effective than DFO. Furthermore, this study also showed that Dp44mT had broad activity, inducing apoptosis in several types of acute leukemia and also multiple myeloma cell lines. Additional studies examining the cytotoxic mechanisms of Dp44mT showed that a reduction in the mitochondrial trans-membrane potential and caspase-3 activation could be involved in the mechanism of apoptosis. Our results suggest that Dp44mT possesses potential as an effective cytotoxic agent for the chemotherapeutic treatment of acute leukemia.
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PMID:Antitumor activity and mechanism of action of the iron chelator, Dp44mT, against leukemic cells. 1914 Jan 86

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