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Publication Record


Nuclear factor-kappa B pathway and response in a phase II trial of bortezomib and docetaxel in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.
Chung CH, Aulino J, Muldowney NJ, Hatakeyama H, Baumann J, Burkey B, Netterville J, Sinard R, Yarbrough WG, Cmelak AJ, Slebos RJ, Shyr Y, Parker J, Gilbert J, Murphy BA
(2010) Ann Oncol 21: 864-870
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Pharmacological, Boronic Acids, Bortezomib, Carcinoma, Squamous Cell, Docetaxel, Female, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms, Humans, Male, Middle Aged, NF-kappa B, Neoplasm Metastasis, Pyrazines, Recurrence, Signal Transduction, Survival Analysis, Taxoids, Treatment Outcome
Show Abstract · Added March 5, 2014
BACKGROUND - Our previous study has shown that nuclear factor-kappa B (NF-kappaB)-signaling pathway was associated with a higher rate of recurrence in head and neck squamous cell carcinoma (HNSCC). The combination of bortezomib, an NF-kappaB inhibitor by inhibition of proteasomes, plus docetaxel was assessed for efficacy and toxicity.
MATERIALS AND METHODS - Patients with recurrent and/or metastatic HNSCC were enrolled on a phase II bortezomib/docetaxel trial (bortezomib 1.6 mg/m(2) and docetaxel 40 mg/m(2) on days 1 and 8 of a 21-day cycle). Response was assessed using RECIST. Tissue specimens were evaluated for the presence of human papillomavirus (HPV) and expression of NF-kappaB-associated genes.
RESULTS - Twenty-one of 25 enrolled patients were assessable for response; one partial response (PR, 5%), 10 stable disease (SD, 48%) and 10 progressive disease (PD, 48%). Patients with PR/SD had significantly longer survival compared with patients with PD and the regimen was well tolerated. Only one of 20 tumors was positive for HPV. Patients with PD had higher expression of NF-kappaB and epidermal growth factor receptor-associated genes in their tumors by gene expression analysis.
CONCLUSION - Further understanding of treatment resistance and interactions between bortezomib and docetaxel may provide novel approaches in managing HNSCC.
0 Communities
4 Members
0 Resources
20 MeSH Terms
Myeloma cells exhibit an increase in proteasome activity and an enhanced response to proteasome inhibition in the bone marrow microenvironment in vivo.
Edwards CM, Lwin ST, Fowler JA, Oyajobi BO, Zhuang J, Bates AL, Mundy GR
(2009) Am J Hematol 84: 268-72
MeSH Terms: Animals, Bone Marrow, Bone Marrow Cells, Boronic Acids, Bortezomib, Cell Communication, Cell Line, Tumor, Enzyme Activation, Immunoglobulin G, Mice, Multiple Myeloma, Neoplasm Transplantation, Protease Inhibitors, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Pyrazines, Tumor Burden
Show Abstract · Added May 13, 2014
The proteasome inhibitor bortezomib has a striking clinical benefit in patients with multiple myeloma. It is unknown whether the bone marrow microenvironment directly contributes to the dramatic response of myeloma cells to proteasome inhibition in vivo. We have used the well-characterized 5TGM1 murine model of myeloma to investigate myeloma growth within bone and response to the proteasome inhibitor bortezomib in vivo. Myeloma cells freshly isolated from the bone marrow of myeloma-bearing mice were found to have an increase in proteasome activity and an enhanced response to in vitro proteasome inhibition, as compared with pre-inoculation myeloma cells. Treatment of myeloma-bearing mice with bortezomib resulted in a greater reduction in tumor burden when the myeloma cells were located within the bone marrow when compared with extra-osseous sites. Our results demonstrate that myeloma cells exhibit an increase in proteasome activity and an enhanced response to bortezomib treatment when located within the bone marrow microenvironment in vivo.
0 Communities
1 Members
0 Resources
17 MeSH Terms
A C-terminal fragment of Cyclin E, generated by caspase-mediated cleavage, is degraded in the absence of a recognizable phosphodegron.
Plesca D, Mazumder S, Gama V, Matsuyama S, Almasan A
(2008) J Biol Chem 283: 30796-803
MeSH Terms: Antigens, Nuclear, Apoptosis, Boronic Acids, Bortezomib, Caspases, Cell Cycle Proteins, Cell Line, Tumor, Cullin Proteins, Cyclin E, DNA-Binding Proteins, F-Box Proteins, F-Box-WD Repeat-Containing Protein 7, Half-Life, Hematologic Neoplasms, Humans, Isoenzymes, Ku Autoantigen, Neoplasm Proteins, Phosphorylation, Protease Inhibitors, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2, Pyrazines, S-Phase Kinase-Associated Proteins, Ubiquitin-Protein Ligases, Ubiquitination, bcl-2-Associated X Protein
Show Abstract · Added October 26, 2015
We have previously shown that caspase-mediated cleavage of Cyclin E generates p18-Cyclin E in hematopoietic tumor cells. Its expression can induce apoptosis or sensitize to apoptotic stimuli in many cell types. However, p18-cyclin E has a much shorter half-life than Cyclin E, being more effectively ubiquitinated and degraded by the 26 S proteasome. A two-step process has emerged that regulates accelerated degradation of Cyclin E, with a caspase-mediated cleavage followed by enhanced proteasome-mediated degradation. We show that recognition of p18-Cyclin E by the Skp1-Cul1-Fbw7 (SCF) complex and its interaction with the Fbw7 protein isoforms can take place independently of phosphorylation of p18-Cyclin E at a C-terminal phosphodegron. In addition to the SCF(Fbw7) pathway, Ku70 binding that facilitates Hdm2 recruitment may also be implicated in p18-Cyclin E ubiquitination. Blocking p18-Cyclin E degradation with proteasome inhibitors increases levels of p18-Cyclin E and enhances its association with Ku70, thus leading to Bax release, its activation, and apoptosis. Moreover, cells expressing p18-Cyclin E are more sensitive to treatment with proteasome inhibitors, such as Bortezomib. By preventing its proteasomal degradation, p18-Cyclin E, but not Cyclin E, may become an effective therapeutic target for Bortezomib and apoptotic effectors in hematopoietic malignancies.
0 Communities
1 Members
0 Resources
27 MeSH Terms
The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis.
Neubert K, Meister S, Moser K, Weisel F, Maseda D, Amann K, Wiethe C, Winkler TH, Kalden JR, Manz RA, Voll RE
(2008) Nat Med 14: 748-55
MeSH Terms: Animals, Boronic Acids, Bortezomib, Lupus Erythematosus, Systemic, Mice, Mice, Inbred BALB C, Mice, Inbred MRL lpr, Mice, Inbred NZB, Models, Immunological, Nephritis, Ovalbumin, Plasma Cells, Protease Inhibitors, Proteasome Inhibitors, Pyrazines, Time Factors
Show Abstract · Added September 17, 2013
Autoantibody-mediated diseases like myasthenia gravis, autoimmune hemolytic anemia and systemic lupus erythematosus represent a therapeutic challenge. In particular, long-lived plasma cells producing autoantibodies resist current therapeutic and experimental approaches. Recently, we showed that the sensitivity of myeloma cells toward proteasome inhibitors directly correlates with their immunoglobulin synthesis rates. Therefore, we hypothesized that normal plasma cells are also hypersensitive to proteasome inhibition owing to their extremely high amount of protein biosynthesis. Here we show that the proteasome inhibitor bortezomib, which is approved for the treatment of multiple myeloma, eliminates both short- and long-lived plasma cells by activation of the terminal unfolded protein response. Treatment with bortezomib depleted plasma cells producing antibodies to double-stranded DNA, eliminated autoantibody production, ameliorated glomerulonephritis and prolonged survival of two mouse strains with lupus-like disease, NZB/W F1 and MRL/lpr mice. Hence, the elimination of autoreactive plasma cells by proteasome inhibitors might represent a new treatment strategy for antibody-mediated diseases.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Proteasome inhibition drastically but reversibly impairs murine lymphocyte development.
Maseda D, Meister S, Neubert K, Herrmann M, Voll RE
(2008) Cell Death Differ 15: 600-12
MeSH Terms: Animals, Apoptosis, B-Lymphocyte Subsets, Bone Marrow Cells, Boronic Acids, Bortezomib, Cells, Cultured, Female, Lymphocyte Count, Lymphoid Tissue, Mice, Mice, Inbred BALB C, NF-kappa B, Precursor Cells, B-Lymphoid, Precursor Cells, T-Lymphoid, Protease Inhibitors, Proteasome Inhibitors, Protein Folding, Pyrazines, T-Lymphocyte Subsets, Thymus Gland
Show Abstract · Added September 17, 2013
The proteasome inhibitor bortezomib, which induces cell death in various cancer cell lines including lymphatic neoplasias, has recently been approved for the treatment of relapsed multiple myeloma. Important mechanisms of proteasome inhibitor-mediated tumor cell death are the inhibition of NF-kappaB activation and induction of the terminal unfolded protein response (UPR). However, little is known about effects of bortezomib on developing and mature lymphocytes. Therefore, Balb/C mice were injected with bortezomib and lymphocyte subsets were analyzed. This treatment resulted in dramatically decreased numbers of T and B lymphocyte precursors, while mature lymphocytes were only partially affected. Thymocytes were almost depleted 3 days after a single bortezomib injection, pro-B and pre-B cells already after 2 days. Thymocytes and B cell precursors recovered within 2 weeks. The decreased numbers of developing lymphocytes were due to apoptotic cell death accompanied by strongly increased caspase 3/7 activity. Within 8 h after bortezomib injection, there was a strong induction of heat shock protein 70 and C/EBP homologous protein in bone marrow B cells, indicating endoplasmic reticulum stress and activation of the terminal UPR, respectively. Hence, induction of apoptosis by proteasome inhibition can dramatically affect lymphocyte development, a fact which has important implications for the clinical use of bortezomib, especially in situations with ongoing lymphopoiesis.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis.
Tai YT, Fulciniti M, Hideshima T, Song W, Leiba M, Li XF, Rumizen M, Burger P, Morrison A, Podar K, Chauhan D, Tassone P, Richardson P, Munshi NC, Ghobrial IM, Anderson KC
(2007) Blood 110: 1656-63
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Bone Marrow Cells, Boronic Acids, Bortezomib, Cell Adhesion, Cell Differentiation, Cell Proliferation, Cell Survival, Cytotoxins, Dexamethasone, Dose-Response Relationship, Drug, Interleukin-6, Lenalidomide, Ligands, MAP Kinase Kinase 1, MAP Kinase Kinase 2, MAP Kinase Signaling System, Macrophage Colony-Stimulating Factor, Mice, Mice, SCID, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Multiple Myeloma, Neoplasm Transplantation, Osteoclasts, Phosphorylcholine, Pyrazines, RANK Ligand, Stromal Cells, Thalidomide, Transplantation, Heterologous, Tumor Cells, Cultured, Xenograft Model Antitumor Assays
Show Abstract · Added November 7, 2019
Activation of the extracellular signal-regulated kinase1/2 (ERK1/2) signaling cascade mediates human multiple myeloma (MM) growth and survival triggered by cytokines and adhesion to bone marrow stromal cells (BMSCs). Here, we examined the effect of AZD6244 (ARRY-142886), a novel and specific MEK1/2 inhibitor, on human MM cell growth in the bone marrow (BM) milieu. AZD6244 blocks constitutive and cytokine-stimulated ERK1/2 phosphorylation and inhibits proliferation and survival of human MM cell lines and patient MM cells, regardless of sensitivity to conventional chemotherapy. Importantly, AZD6244 (200 nM) induces apoptosis in patient MM cells, even in the presence of exogenous interleukin-6 or BMSCs associated with triggering of caspase 3 activity. AZD6244 sensitizes MM cells to both conventional (dexamethasone) and novel (perifosine, lenalidomide, and bortezomib) therapies. AZD6244 down-regulates the expression/secretion of osteoclast (OC)-activating factors from MM cells and inhibits in vitro differentiation of MM patient PBMCs to OCs induced by ligand for receptor activator of NF-kappaB (RANKL) and macrophage-colony stimulating factor (M-CSF). Finally, AZD6244 inhibits tumor growth and prolongs survival in vivo in a human plasmacytoma xenograft model. Taken together, these results show that AZD6244 targets both MM cells and OCs in the BM microenvironment, providing the preclinical framework for clinical trials to improve patient outcome in MM.
0 Communities
1 Members
0 Resources
MeSH Terms
Augmenting chemosensitivity of malignant melanoma tumors via proteasome inhibition: implication for bortezomib (VELCADE, PS-341) as a therapeutic agent for malignant melanoma.
Amiri KI, Horton LW, LaFleur BJ, Sosman JA, Richmond A
(2004) Cancer Res 64: 4912-8
MeSH Terms: Active Transport, Cell Nucleus, Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Boronic Acids, Bortezomib, Cell Division, Cell Line, Tumor, Dacarbazine, Drug Synergism, Female, Gene Expression, Humans, Melanoma, Mice, Mice, Inbred BALB C, NF-kappa B, Neovascularization, Pathologic, Protease Inhibitors, Pyrazines, Temozolomide
Show Abstract · Added June 14, 2013
Melanoma poses a great challenge to patients, oncologists, and biologists because of its nearly universal resistance to chemotherapy. Many studies have shown that nuclear factor kappaB is constitutively activated in melanoma, thereby promoting the proliferation of melanoma cells by inhibiting the apoptotic responses to chemotherapy. Nuclear factor kappaB activity is regulated by phosphorylation and subsequent degradation of inhibitor of nuclear factor kappaB by the ubiquitin-proteasome pathway. In this study, we show that the novel proteasome inhibitor, bortezomib, inhibited the growth of melanoma cells in vitro at a concentration range of 0.1-10 nM and in combination with the chemotherapeutic agent temozolomide, the inhibitory effect on melanoma cell growth was even more prominent. Data from a murine model showed reduced tumor growth when bortezomib was administered to human melanoma tumors. Strikingly, animals receiving bortezomib in combination with temozolomide achieved complete remission of palpable tumors after only 30 days of therapy, lasting >200 days. Our data indicate strongly that bortezomib in combination with chemotherapeutic agents should be studied additionally for the treatment of melanoma.
2 Communities
3 Members
0 Resources
22 MeSH Terms
Thiolytic chemistry of alternative precursors to the major metabolite of the cancer chemopreventive oltipraz.
Navamal M, McGrath C, Stewart J, Blans P, Villamena F, Zweier J, Fishbein JC
(2002) J Org Chem 67: 9406-13
MeSH Terms: Algorithms, Anticarcinogenic Agents, Chromatography, High Pressure Liquid, Electron Spin Resonance Spectroscopy, Free Radicals, Glutathione, Kinetics, Models, Molecular, Molecular Structure, Pyrazines, Sulfhydryl Compounds
Show Abstract · Added January 27, 2012
The compounds 7-methyl-6,8-bis(methyldisulfanyl)pyrrolo[1,2-a]pyrazine (5; "bis disulfide") and methanethiosulfonic acid S-((6-(methanesulfonylsulfanyl)-7-methyl)pyrrolo[1,2-a]pyrazin-8-yl) ester (6; "bis methanesulfonic acid thioester") have been synthesized to serve as alternative precursors to the major metabolite, 4, of the cancer chemopreventive oltipraz, 1, to test whether they possess similar biological activities. In the present work the mechanisms by which these compounds react with glutathione have been investigated in order to validate the assumption that they would be chemically competent in the presence of the biological thiols to give the oltipraz metabolite. A kinetic and product study was carried out in mainly aqueous media,
0 Communities
1 Members
0 Resources
11 MeSH Terms
CI-980 in advanced melanoma and hormone refractory prostate cancer.
Ryan CW, Shulman KL, Richards JM, Kugler JW, Sosman JA, Ansari RH, Vokes EE, Vogelzang NJ
(2000) Invest New Drugs 18: 187-91
MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Carbamates, Drug Resistance, Neoplasm, Female, Humans, Male, Melanoma, Middle Aged, Prostatic Neoplasms, Pyrazines, Pyridines
Show Abstract · Added March 5, 2014
INTRODUCTION - CI-980 is a novel chemotherapeutic agent that inhibits polymerization of tubulin. Preclinical studies have indicated a high level activity of this agent against various tumor cell lines.
METHODS - 13 malignant melanoma patients who had failed prior chemotherapy and/or immunotherapy and 13 hormone refractory prostate cancer patients, including 4 who had received prior chemotherapy, were treated in 2 separate NCI-supported clinical trials. Subjects received a recommended phase II dose of CI-980 of 4.5 mg/m2/day by continuous infusion for 72 hours every 3 weeks.
RESULTS - No activity was seen in either study. Toxicity was tolerable with neutropenia being the most common, significant toxicity. Among the melanoma patients, 15% and 31% developed grade 3 and grade 4 neutropenia, while 7% and 38% of the prostate patients developed grade 3 and grade 4 neutropenia, respectively.
CONCLUSIONS - CI-980 at this dose and schedule is ineffective against malignant melanoma and hormone refractory prostate cancer.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Inhibition of human cytochrome P450 enzymes by 1,2-dithiole-3-thione, oltipraz and its derivatives, and sulforaphane.
Langou√ęt S, Furge LL, Kerriguy N, Nakamura K, Guillouzo A, Guengerich FP
(2000) Chem Res Toxicol 13: 245-52
MeSH Terms: Anticarcinogenic Agents, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 Enzyme Inhibitors, Humans, Isothiocyanates, Pyrazines, Quinolines, Thiocyanates, Thiones, Thiophenes
Show Abstract · Added May 26, 2014
Recent studies have demonstrated that two chemoprotective agents, oltipraz (OPZ), a synthetic derivative of the natural compound 1, 2-dithiole-3-thione (D3T), and sulforaphane (SF), an isothiocyanate, are not only inducers of glutathione S-transferases but also inhibitors of some major cytochrome P450 enzymes (P450s) involved in xenobiotic metabolism. We examined P450 inhibition by the two compounds and compared two OPZ metabolites (OPZ M(3) and M(8)) and D3T using human P450s expressed in Escherichia coli membranes. OPZ was a more potent inhibitor than D3T or SF, in the following order of inhibition: P450 1A2 > 3A4 > 1A1 approximately 1B1 > 2E1. OPZ M(3) also inhibited P450s 1A2, 1A1, 1B1, and 3A4 but not more effectively than OPZ. OPZ M(8) was not inhibitory. OPZ behaved as a competitive inhibitor of P450 1A2, with a K(i) of 1.5 microM. Incubation of P450 1A2 with OPZ and NADPH led to a first-order loss of the P450 spectrum, and the loss was not blocked by glutathione. No such time-dependent loss of P450 was seen with P450 1A2 and D3T, P450 1A2 and OPZ M(3), P450 1A2 and SF, P450 3A4 and OPZ, P450 3A4 and D3T, P450 2E1 and OPZ, or P450 2E1 and D3T. The time- and concentration-dependent loss of P450 1A2 activity in the presence of OPZ was characterized with a K(i) of 9 microM and a k(inactivation) of 0.19 min(-)(1). The activation of 2-amino-3,5-dimethylimidazo[4, 5-f]quinoline (MeIQ) in an E. coli lac-based mutagenicity tester system containing functional human P450 1A2 was inhibited by OPZ (IC(50) < 1 microM) but not appreciably by 40 microM D3T. Our results indicate that OPZ is a competitive and mechanism-based inhibitor of P450 1A2, and the extent of this inhibition is significantly greater than that of other chemoprotective chemicals with P450 1A2 or other human P450s.
0 Communities
1 Members
0 Resources
10 MeSH Terms