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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bortezomib is a novel anti-cancer agent which has shown promising activity in non-small lung cancer (NSCLC) patients. However, only a subset of patients respond to this treatment. We show that NSCLC cell lines are differentially sensitive to bortezomib, IC50 values ranging from 5 to 83 nM. The apoptosis-inducing potential of bortezomib in NSCLC cells was found to be dependent not only on the apoptotic phenotype but also on the proteasomal phenotype of individual cell lines. Upon effective proteasome inhibition, H460 cells were more susceptible to apoptosis induction by bortezomib than SW1573 cells, indicating a different apoptotic phenotype. However, exposure to a low dose of bortezomib did only result in SW1573 cells, and not in H460 cells, in inhibition of proteasome activity and subsequent apoptosis. This suggests a different proteasomal phenotype as well. Additionally, overexpression of anti-apoptotic protein Bcl-2 in H460 cells did not affect the proteasomal phenotype of H460 cells but did result in decreased bortezomib-induced apoptosis. In conclusion, successful proteasome-inhibitor based treatment strategies in NSCLC face the challenge of having to overcome apoptosis resistance as well as proteasomal resistance of individual lung cancer cells. Further studies in NSCLC are warranted to elucidate underlying mechanisms.
Mol Cancer 2007 Nov 17
PMID:The proteasomal and apoptotic phenotype determine bortezomib sensitivity of non-small cell lung cancer cells. 1802 20

In congestive heart failure (CHF), diaphragm weakness is known to occur and is associated with myosin loss and activation of the ubiquitin-proteasome pathway. The effect of modulating proteasome activity on myosin loss and diaphragm function is unknown. The present study investigated the effect of in vivo proteasome inhibition on myosin loss and diaphragm function in CHF rats. Coronary artery ligation was used as an animal model for CHF. Sham-operated rats served as controls. Animals were treated with the proteasome inhibitor bortezomib (intravenously) or received saline (0.9%) injections. Force generating capacity, cross-bridge cycling kinetics, and myosin content were measured in diaphragm single fibers. Proteasome activity, caspase-3 activity, and MuRF-1 and MAFbx mRNA levels were determined in diaphragm homogenates. Proteasome activities in the diaphragm were significantly reduced by bortezomib. Bortezomib treatment significantly improved diaphragm single fiber force generating capacity (approximately 30-40%) and cross-bridge cycling kinetics (approximately 20%) in CHF. Myosin content was approximately 30% higher in diaphragm fibers from bortezomib-treated CHF rats than saline. Caspase-3 activity was decreased in diaphragm homogenates from bortezomib-treated rats. CHF increased MuRF-1 and MAFbx mRNA expression in the diaphragm, and bortezomib treatment diminished this rise. The present study demonstrates that treatment with a clinically used proteasome inhibitor improves diaphragm function by restoring myosin content in CHF.
Am J Physiol Lung Cell Mol Physiol 2008 Jun
PMID:Proteasome inhibition improves diaphragm function in congestive heart failure rats. 1842 22

Nuclear factor-kappaB (NF-kappaB) influences the initiation, progression, and maintenance of diverse cancer types. Despite current therapeutic efforts to block hyperactive NF-kappaB in cancer cells, the in vivo effects of a drug upon this complex pathway are unclear. We monitored NF-kappaB activity and a fast-expressing reporter level simultaneously in head and neck squamous carcinoma cells by quantitative live microscopy. The real-time single cell assay revealed the tumor necrosis factor-alpha-induced oscillation of NF-kappaB was echoed by equally dynamic reporter expression rate. Bortezomib is a proteasome inhibitor whose anticancer action is partly mediated through inhibition of NF-kappaB. When administered to preactivated cells, the drug gave rise to distinct inhibition dynamics, with discrete pulses of reporter induction remaining for hours. These findings suggest that, contrary to a simplistic presumption for a pathway "blockade," the network dynamics and the intracellular pharmacokinetics of the inhibitor must be critically evaluated in developing strategies for optimal intervention of oncogenic pathways.
Mol Pharmacol 2008 Nov
PMID:Dynamic effect of bortezomib on nuclear factor-kappaB activity and gene expression in tumor cells. 1868 39

Bortezomib (Velcade/PS341), a proteasome inhibitor used in the treatment of multiple myeloma (MM), can inhibit activation of nuclear factor-kappaB (NF-kappaB), a family of transcription factors often deregulated and constitutively activated in primary MM cells. NF-kappaB can be activated via several distinct mechanisms, including the proteasome inhibitor-resistant (PIR) pathway. It remains unknown what fraction of primary MM cells harbor constitutive NF-kappaB activity maintained by proteasome-dependent mechanisms. Here, we report an unexpected finding that constitutive NF-kappaB activity in 10 of 14 primary MM samples analyzed is refractory to inhibition by bortezomib. Moreover, when MM cells were cocultured with MM patient-derived bone marrow stromal cells (BMSC), microenvironment components critical for MM growth and survival, further increases in NF-kappaB activity were observed that were also refractory to bortezomib. Similarly, MM-BMSCs caused PIR NF-kappaB activation in the RPMI8226 MM cell line, leading to increased NF-kappaB-dependent transcription and resistance to bortezomib-induced apoptosis. Our findings show that primary MM cells frequently harbor PIR NF-kappaB activity that is further enhanced by the presence of patient-derived BMSCs. They also suggest that this activity is likely relevant to the drug resistance development in some patients. Further elucidation of the mechanism of PIR NF-kappaB regulation could lead to the identification of novel diagnostic biomarkers and/or therapeutic targets for MM treatment.
Mol Cancer Res 2008 Aug
PMID:Bortezomib-resistant nuclear factor-kappaB activity in multiple myeloma cells. 1870 67

Esophageal squamous cell carcinoma (ESCC) is an exceptionally drug-resistant tumor with a 5-year survival rate <5%. From an initial drug screen, we identified bortezomib as having robust activity in ESCC lines. Mechanistically, bortezomib induced a G2-M-phase cell cycle arrest and p53-independent apoptosis associated with caspase cleavage and Noxa induction. Bortezomib also showed excellent activity in organotypic culture and in vivo models of ESCC. Biochemically, bortezomib treatment activated the p38 and c-Jun NH2-termnial kinase stress-activated mitogen-activated protein kinase (MAPK) pathways and induced phospho-H2AX activity. Although H2AX is known to cooperate with c-Jun NH2-termnial kinase to induce apoptosis following UV irradiation, knockdown of H2AX did not abrogate bortezomib-induced apoptosis. Instead, blockade of p38 MAPK signaling, using either small interfering RNA or a pharmacologic inhibitor, reversed bortezomib-induced apoptosis and the up-regulation of Noxa. Radiation therapy is known to activate the p38 MAPK pathway and is a mainstay of ESCC treatment strategies. In a final series of studies, we showed that the coadministration of bortezomib with irradiation led to enhanced p38 MAPK activity and a significant reduction in colony formation. We therefore suggest that p38 MAPK pathway activation is an excellent potential therapeutic strategy in ESCC. It is further suggested that bortezomib could be added to existing ESCC therapeutic regimens.
Mol Cancer Ther 2008 Sep
PMID:Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway. 1879 Jul 67

The purpose of the present study was to evaluate the potency of the proteasome inhibitor bortezomib +/- gemcitabine in vitro and in vivo in pancreatic carcinoma. It could be shown that bortezomib induced apoptosis and inhibited proliferation of pancreatic carcinoma very efficiently in vitro. In contrast, in an orthotopic pancreatic adenocarcinoma mouse model, gemcitabine treatment inhibited tumor growth, whereas bortezomib promoted it. Bortezomib-treated animals showed significantly higher tumor burden compared with gemcitabine-treated and control animals, although bortezomib was locally active and induced a decrease of proteasome activity, which was most pronounced following the simultaneous administration of gemcitabine. Also, tumor progression was not caused by immunosuppression as a result of proteasome inhibition. Interestingly, anti-CD31 staining of tumors showed that angiogenesis was significantly increased in the tumors of bortezomib-treated mice compared with the tumors of control animals. In addition, bortezomib resulted an increase of pericytes, vascular endothelial growth factor, RGS-5, and hypoxia-inducible factor-1alpha in the tumor. Although this study supports efficacy of bortezomib against pancreatic carcinoma in vitro, it strongly indicates that bortezomib therapy has a significant tumor-promoting effect in vivo by induction of angiogenesis. The data are in accordance with the complete failure of bortezomib in a phase II trial for this indication. Choosing the right schedule of gemcitabine and bortezomib showed some synergistic effects, but the gain might not be big enough to compensate the potentially detrimental effects.
Mol Cancer Ther 2008 Nov
PMID:Bortezomib is ineffective in an orthotopic mouse model of pancreatic adenocarcinoma. 1900 44

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.
Int J Mol Med 2008 Dec
PMID:Differential sensitivity of breast cancer and melanoma cells to proteasome inhibitor Velcade. 1902 Jul 81

The proteasome inhibitor bortezomib (PS-341/Velcade) is used for the treatment of relapsed and refractory multiple myeloma and mantle-cell lymphoma. We recently reported its therapeutic potential against natural killer (NK)-cell neoplasms. Here, we investigated the molecular mechanisms of bortezomib-induced cell death in NK lymphoma cells. NK lymphoma cell lines (SNK-6 and NK-YS) and primary cultures of NK lymphomas treated with bortezomib were examined for alterations in cell viability, apoptosis, cellular senescence, and cell cycle status. Bortezomib primarily induced mitochondrial apoptosis in NK-YS cells and in primary lymphoma cells at the same concentration as reported in myeloma cells. Unexpectedly, SNK-6 cells required a significantly higher median inhibitory concentration of bortezomib (23 nmol/L) than NK-YS and primary lymphoma cells (6-13 nmol/L). Apoptosis was limited in SNK-6 cells due to the extensively delayed turnover of Bcl-2 family members. These cells were killed by bortezomib, albeit at higher pharmacologic concentrations, via mitotic catastrophe-a mitotic cell death associated with M-phase arrest, cyclin B1 accumulation, and increased CDC2/CDK1 activity. Our results suggest that, in addition to cell death by apoptosis at lower bortezomib concentrations, NK lymphoma cells resistant to bortezomib-induced apoptosis can be killed via mitotic catastrophe, an alternative cell death mechanism, at higher pharmacologic concentrations of bortezomib. Hence, activating mitotic catastrophe by bortezomib may provide a novel therapeutic approach for treating apoptosis-resistant NK-cell malignancies and other cancers.
Mol Cancer Ther 2008 Dec
PMID:Cell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells. 1907 55

The aim of the current study is to determine whether butein (3,4,2',4'-tetrahydroxychalcone) exhibits antiproliferative effects against tumor cells through suppression of the signal transducer and activator of transcription 3 (STAT3) activation pathway. We investigated the effects of butein on constitutive and inducible STAT3 activation, role of tyrosine kinases and phosphatases in STAT3 activation, STAT3-regulated gene products, and growth modulation of tumor cells. We found that this chalcone inhibited both constitutive and interleukin-6-inducible STAT3 activation in multiple myeloma (MM) cells. The suppression was mediated through the inhibition of activation of the upstream kinases c-Src, Janus-like kinase (JAK) 1, and JAK2. Vanadate treatment reversed the butein-induced down-regulation of STAT3 activation, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that butein induced the expression of the tyrosine phosphatase SHP-1 and deletion of SHP-1 gene by small interfering RNA abolished the ability of butein to inhibit STAT3 activation, suggesting the critical role of SHP-1 in the action of this chalcone. Butein down-regulated the expression of STAT3-regulated gene products such as Bcl-xL, Bcl-2, cyclin D1, and Mcl-1, and this led to the suppression of proliferation and induction of apoptosis. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the butein-induced apoptosis. Moreover, we found that butein significantly potentiated the apoptotic effects of thalidomide and Velcade in MM cells. Overall, these results suggest that butein is a novel blocker of STAT3 activation and thus may have potential in suppression of tumor cell proliferation and reversal of chemoresistance in MM cells.
Mol Pharmacol 2009 Mar
PMID:Butein suppresses constitutive and inducible signal transducer and activator of transcription (STAT) 3 activation and STAT3-regulated gene products through the induction of a protein tyrosine phosphatase SHP-1. 1910 60

Mapatumumab and lexatumumab are fully human monoclonal antibodies that bind and activate human tumor necrosis factor-related apoptosis-inducing ligand receptors 1 and 2, respectively. These antibodies induce apoptosis in various tumor cell types, although the degree of sensitivity can vary from highly sensitive to completely resistant. Importantly, tumor cells that are partially or completely resistant to mapatumumab or lexatumumab can often be sensitized when treated in combination with chemotherapeutic drugs. In this regard, the proteasome inhibitor bortezomib has recently shown synergistic activity against established lymphoma cell lines and primary lymphomas when combined with mapatumumab and lexatumumab. Here, we report similar findings using a panel of human non-small cell lung cancer (NSCLC) cell lines. Specifically, we show that bortezomib rapidly induces sensitivity to mapatumumab and lexatumumab in NSCLC cell lines that are completely resistant to antibody alone and that bortezomib concentrations as low as 25 nmol/L sensitize NSCLC cells to the antibodies. Furthermore, bortezomib at the tested concentration has minimal effect on its own, indicating the combination generates synergistic cytotoxicity. Combination treatment induces activation of the caspase cascade and the effect of the combination is caspase dependent. Bortezomib treatment increases the intracellular levels of several important apoptosis regulators that may mediate enhanced sensitivity to mapatumumab and lexatumumab. These results suggest future evaluation of mapatumumab or lexatumumab in combination with bortezomib is warranted in NSCLC patients.
Mol Cancer Ther 2009 Feb
PMID:Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib. 1917 54


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