The Experts below are selected from a list of 4503 Experts worldwide ranked by ideXlab platform
Zhimin Shao - One of the best experts on this subject based on the ideXlab platform.
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TIEG1 induces apoptosis through mitochondrial apoptotic pathway and promotes apoptosis induced by homoharringtonine and Velcade
FEBS Letters, 2007Co-Authors: Genhong Di, Tiewei Cheng, Jiong Wu, Junjie Li, Wen Feng Li, Ying Chen, Zhimin ShaoAbstract:Overexpression of TGFβ inducible early gene (TIEG1) mimics TGFβ action and induces apoptosis. In this study, we found that TIEG1 was significantly up-regulated during apoptosis induced by homoharringtonine or Velcade. Overexpression of TIEG1 could induce apoptosis in K562 cells and promote apoptosis induced by HHT or Velcade. TIEG1-induced apoptosis was shown to involve Bax and Bim up-regulation, Bcl-2 and Bcl-XL down-regulation, release of cytochrome c from mitochondria into the cytosol, activation of caspase 3 and disruption of the mitochondrial membrane potential (ΔΨm). We concluded that TIEG1 is a key regulator which induces and promotes apoptosis through the mitochondrial apoptotic pathway.
Dai-wu Seol - One of the best experts on this subject based on the ideXlab platform.
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p53-Independent up-regulation of a TRAIL receptor DR5 by proteasome inhibitors: a mechanism for proteasome inhibitor-enhanced TRAIL-induced apoptosis.
Biochemical and biophysical research communications, 2011Co-Authors: Dai-wu SeolAbstract:Gliomas are the most common brain tumors in adults and account for more than half of all brain tumors. Despite intensive clinical investigations, average survival for the patients harboring the malignancy has not been significantly improved. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), shown to have potent and cancer-selective killing activity, has drawn considerable attention as a promising anti-cancer therapy. In an attempt to develop TRAIL as an anti-cancer therapy for gliomas, tumor suppressor activity of TRAIL was assessed using human glioma cell lines such as U373MG, U343MG, U87MG and LN18. U343MG, U87MG and LN18 cells were susceptible to TRAIL; however, U373MG cells were completely refractory to TRAIL. Resistance to the applied therapies is a key issue in cancer treatment; thus, various combination treatments were evaluated using U373MG cells to identify a better regimen. Unlike Doxorubicin, Etoposide, Actinomycin D and Wortmannin, a proteasome inhibitor MG132 significantly enhanced TRAIL-induced apoptosis. Similarly, other proteasome inhibitors, including Lactacystin, Proteasome inhibitor I and Velcade (Bortezomib), also enhanced apoptotic activity of TRAIL. Among these proteasome inhibitors, Velcade, the only approved drug, was as effective as MG132 in enhancing TRAIL-induced apoptosis. Both Velcade and MG132 increased the protein levels of DR5, a TRAIL receptor known to be up-regulated by p53, in U373MG cells where p53 is mutated. Our data indicate that proteasome inhibitors up-regulate DR5 in a p53-independent manner and a combination therapy comprising TRAIL and Velcade become a better treatment regimen for gliomas.
Steven R. Schwarze - One of the best experts on this subject based on the ideXlab platform.
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Velcade sensitizes prostate cancer cells to TRAIL induced apoptosis and suppresses tumor growth in vivo.
Cancer biology & therapy, 2009Co-Authors: Perry A. Christian, Jeffery A. Thorpe, Steven R. SchwarzeAbstract:Inducing apoptosis via the extrinsic death receptor pathway is an attractive anti-cancer treatment strategy, however, numerous cancer cells exhibit significant resistance to death ligand stimuli. Here, we investigated the anti-neoplastic capability of proteasome inhibition, through the administration of Velcade, to synergize with a death receptor agonist in vivo. The death ligand-resistant LNCaP prostate xenograft model was utilized. Tumors were established and mice were treated with Velcade, TRAIL (TNF-Related Apoptosis Inducing Ligand) or the combined regimen. Only mice treated with a combination of Velcade and TRAIL was tumor growth inhibited with a corresponding loss of the hemorrhagic phenotype, decreased tumor cell proliferation and increased tumor cell apoptosis. Next, to determine if the extrinsic pathway is critical for mediating the anti-tumor efficacy that can be achieved in some cell types with Velcade treatment alone, the death receptor sensitive PC-3 xenograft model was used. PC-3 tumors exhibited a 54% decrease in tumor volume in response to Velcade, while c-FLIP overexpressing PC-3 xenografts were resistant to the treatment. These findings suggest that the extrinsic apoptotic pathway can mediate the anti-tumor effects of Velcade and support the therapeutic use of proteasome inhibition in combination with a death receptor stimulus in the treatment of prostate cancer.
Michael Chopp - One of the best experts on this subject based on the ideXlab platform.
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Combination Therapy With Velcade and Tissue Plasminogen Activator Is Neuroprotective in Aged Rats After Stroke and Targets MicroRNA-146a and the Toll-Like Receptor Signaling Pathway
Arteriosclerosis thrombosis and vascular biology, 2012Co-Authors: Li Zhang, Michael Chopp, Hua Teng, Xianshuang Liu, Tao Tang, Haifa Kassis, Zheng Gang ZhangAbstract:Objective—Activation of the toll-like receptor (TLR) signaling pathway exacerbates ischemic brain damage. The present study tested the hypothesis that combination treatment with Velcade and tissue plasminogen activator (tPA) modulates the TLR signaling pathway on cerebral vasculature, which leads to neuroprotection in aged rats after stroke. Methods and Results—Focal cerebral ischemia acutely increased TLR2, TLR4, and interleukin-1 receptor–activated kinases 1 immunoreactivity on fibrin/fibrinogen-positive vessels in aged rats. Monotherapy of tPA further amplified these signals. However, Velcade in combination with tPA-blocked stroke- and tPA-potentiated vascular TLR signals, leading to robust reduction of infarct volume compared with respective monotherapies. Quantitative reverse transcription polymerase chain reaction analysis of cerebral endothelial cells isolated by laser capture microdissection revealed that the combination treatment increased miR-l46a levels, which was inversely associated with the ...
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Abstract 2966: Role of the Cerebral Vascular Toll-Like Receptor Signaling Pathway in Neuroprotection Induced by Combination Therapy of Velcade and TPA
Stroke, 2012Co-Authors: Li Zhang, Zheng Gang Zhang, Hua Teng, Xianshuang Liu, Michael ChoppAbstract:Background and Purpose: Toll-like receptors (TLRs) and their family members including IL-1 receptor-associated kinase-1 (IRAK1) mediate ischemic cell damage. MicroRNAs (miRNAs) including miR-146a regulate TLRs. The present study investigated whether treatment of stroke in older animals with Velcade in combination with tPA affects expression of TLRs and miR-146a in cerebral endothelial cells. Methods: Wistar rats at the age of 16-18 months were subjected to right embolic middle cerebral artery occlusion (MCAo). Velcade (0.1mg/kg) and tPA (5mg/kg) were intravenously administered 2h after MCAo (n=16). Ischemic rats treated with tPA alone (n=14) or saline (n=15) were used as control groups. Levels of TLRs and miR-146a in cerebral endothelial cells were measured. Cultured primary cerebral endothelial cells (PCECs) were used for investigating the direct effect of Velcade on expression of miR-146a. Results: Quantitative RT-PCR analysis revealed that Velcade in combination with tPA significantly increased miR-l46a levels (11±3 fold) in the cerebral endothelial cells isolated by laser capture microdissection compared with that in ischemic rats treated with tPA monotherapy (2±1). Concurrently, immunostaining showed that the combination therapy suppressed tPA monotherapy-upregulated TLR2 (44±7 vs 93±8/mm 2 in tPA), TLR4 (39±6vs 91±8), IRAK1 (16±3 vs 46±5), fibrin (17±6 vs 40±3), and NF-kB (9±2 vs 22±3) immunoreactive vessels, leading to reduction of infarct volume (14±2 vs 28±3% in tPA, and 30±3% in saline, p Conclusion: Our data demonstrate that fibrin activates endothelial TLRs and that Velcade-upregulated miR-146a abolishes tPA-induced TLRs, suggesting that miRNAs and the TLR signaling pathway in cerebral endothelial cells play an important role in the neuroprotective effect of the combination therapy of Velcade and tPA for acute stroke.
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The treatment of traumatic brain injury with Velcade.
Journal of neurotrauma, 2010Co-Authors: Asim Mahmood, Ruizhuo Ning, Ye Xiong, Li Zhang, Jieli Chen, Hao Jiang, Michael ChoppAbstract:Abstract Traumatic brain injury (TBI) elicits a strong inflammatory response that contributes to the acute pathological processes seen following TBI, including cerebral edema and disruption of the blood–brain barrier (BBB), in addition to longer-term neurological damage and cognitive impairment. Proteasome inhibitors reduce vascular thrombotic and inflammatory events and consequently protect vascular function. In the present study we evaluated the neuroprotective effect of Velcade® (bortezomib), a potent and selective inhibitor of proteasomes, which is in clinical use for the treatment of multiple myeloma. When administered within 2 h after TBI onset, Velcade reduced inflammatory responses, lesion volume, and neurological functional deficits, and enhanced neuronal survival. Western blot and ELISA showed that Velcade decreased the expression of NF-κB. These results suggest that in the experimental setting, Velcade is an effective neuroprotective agent for the treatment of TBI.
Andrzej Jakubowiak - One of the best experts on this subject based on the ideXlab platform.
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lenalidomide bortezomib pegylated liposomal doxorubicin hydrochloride and dexamethasone in newly diagnosed multiple myeloma initial results of phase i ii mmrc trial
Journal of Clinical Oncology, 2009Co-Authors: Andrzej Jakubowiak, Mark S. Kaminski, Craig C Hofmeister, Erica L Campagnaro, Todd M Zimmerman, Robert Schlossman, S Lonial, D Reece, K C Anderson, P G RichardsonAbstract:8517 Background: Three-drug combinations with lenalidomide (Revlimid, Rev) and bortezomib (Velcade, Vel) are highly active in previously untreated multiple myeloma (MM). Among the most active are R...
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Gene Expression Profiles (GEP) To Predict at Least Very Good Partial Response to Velcade, Doxil, and Dexamethasone in Newly Diagnosed Patients with Multiple Myeloma.
Blood, 2007Co-Authors: Malathi Hari, Tara Kendall, Judah Friedman, James W. Macdonald, George Mulligan, Andrzej JakubowiakAbstract:The introduction of novel agents and combination treatments in multiple myeloma (MM) has dramatically improved overall response rates and quality of responses including rates of complete and near complete response (CR/nCR) and very good partial response (VGPR). There is emerging evidence that achieving at least ≥90% disease reduction (≥ VGPR) at some point of treatment is associated with improved outcome and longer survival. Therefore, there is a need to identify patients who will likely achieve this level of reduction of disease and therefore who will have a higher likelihood of benefiting from the specific treatments. In the current study, we evaluated GEP of MM cells obtained from patients who were enrolled in a phase II clinical trial of the frontline therapy with a combination with bortezomib (Velcade), liposomal doxorubicin (Doxil) and dexamethasone (VDD). The primary objective of this research is to develop predictive biomarkers of response to VDD by identifying GEP of patient who achieve ≥ VGPR. Forty newly diagnosed patients were enrolled in the trial. The regimen was given for six 3-week cycles as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and dexamethasone at 40 mg on days 1–4 for the first 10 patients and for the remaining patients at 20 mg on days of Velcade and the day after. Updated results from 40/40 evaluable patients show 93% partial response rate (≥ PR) with 43% CR/nCR and 63% > VGPR (Jakubowiak et al., IMW 2007, Abstract PO-721). Bone marrow aspirates were obtained before therapy from patients who had given an optional consent for research samples. MM cells were negatively selected using RossetteSep myeloma antibody cocktail. Gene expression profiling was performed with 20 samples using Affymetrix Human Genome U133 Plus 2.0 microarray, of which 19 samples were evaluable. These samples were classified based on the modified uniform response criteria with an addition of nCR and minor response (MR) (Durie et al, Leukemia 2006;20:1467) as either ≥ VGPR, (includes VGPR and CR/nCR), or
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gene expression profiles gep to predict at least very good partial response to Velcade doxil and dexamethasone in newly diagnosed patients with multiple myeloma
Blood, 2007Co-Authors: Malathi Hari, Tara Kendall, Judah Friedman, James W. Macdonald, George Mulligan, Andrzej JakubowiakAbstract:The introduction of novel agents and combination treatments in multiple myeloma (MM) has dramatically improved overall response rates and quality of responses including rates of complete and near complete response (CR/nCR) and very good partial response (VGPR). There is emerging evidence that achieving at least ≥90% disease reduction (≥ VGPR) at some point of treatment is associated with improved outcome and longer survival. Therefore, there is a need to identify patients who will likely achieve this level of reduction of disease and therefore who will have a higher likelihood of benefiting from the specific treatments. In the current study, we evaluated GEP of MM cells obtained from patients who were enrolled in a phase II clinical trial of the frontline therapy with a combination with bortezomib (Velcade), liposomal doxorubicin (Doxil) and dexamethasone (VDD). The primary objective of this research is to develop predictive biomarkers of response to VDD by identifying GEP of patient who achieve ≥ VGPR. Forty newly diagnosed patients were enrolled in the trial. The regimen was given for six 3-week cycles as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and dexamethasone at 40 mg on days 1–4 for the first 10 patients and for the remaining patients at 20 mg on days of Velcade and the day after. Updated results from 40/40 evaluable patients show 93% partial response rate (≥ PR) with 43% CR/nCR and 63% > VGPR (Jakubowiak et al., IMW 2007, Abstract PO-721). Bone marrow aspirates were obtained before therapy from patients who had given an optional consent for research samples. MM cells were negatively selected using RossetteSep myeloma antibody cocktail. Gene expression profiling was performed with 20 samples using Affymetrix Human Genome U133 Plus 2.0 microarray, of which 19 samples were evaluable. These samples were classified based on the modified uniform response criteria with an addition of nCR and minor response (MR) (Durie et al, Leukemia 2006;20:1467) as either ≥ VGPR, (includes VGPR and CR/nCR), or
Velcade alone. The study described here provides evidence that GEPs of samples derived from patients before treatment is a useful tool in clinical trials to prospectively evaluate MM patients for individualized therapy with the goal of minimizing toxicity and maximizing efficacy. -
Combination Therapy with Velcade, Doxil, and Dexamethasone (VDD) for Patients with Relapsed/Refractory Multiple Myeloma (MM).
Blood, 2005Co-Authors: Andrzej Jakubowiak, Lindsey Brackett, Tara Kendall, Judah Friedman, Mark S. KaminskiAbstract:Background: Combination regimens with Velcade demonstrate high activity in both relapsed/refractory and newly diagnosed MM, including higher than previously observed rates of complete responses (CR) and near complete responses (nCR). In this study, we evaluated the activity of a combination of Velcade, Doxil, and Dexamethasone (VDD) in relapsed/refractory MM. The rationale for combining these 3 agents was provided in pre-clinical studies which showed that Velcade can synergize with DNA-damaging agents via caspase-8 pathway and with Dexamethasone via caspase-9 pathway. In addition, prior clinical studies showed that combinations of Velcade with either Doxil or dexamethasone are well tolerated and more active than Velcade alone. The primary objective of the study was to assess the overall response to VDD and to estimate whether this combination can improve the rate of CR and nCR. Methods: The trial opened in November 2004 with target accrual of 30 patients. EBMT criteria were used for evaluation of response and nCR was defined as M-protein reduced to a level detectable by only immunofixation. The regimen in both relapsed/refractory and frontline trials was given as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and Dexamethasone at 40 mg orally on days 1–4. VDD was repeated every 3 weeks for a total of 6 cycles. After the completion of 6 cycles, patients in the relapsed/refractory trial were maintained on Velcade weekly and Dexamethasone on days 1–4 in 5-week cycles. Results: To date, 20 pts have been enrolled, 18 of whom are presently evaluable for response after receiving a mean of 3.6 cycles (range 1–6). The characteristics of the evaluable patients included the following: median age 62 (range 39–78), 1–5 prior lines of therapy, single autologous stem cell transplant in 14 patients, tandem transplant in 1 patient, allogeneic transplant in 1 patient, chromosome 13 deletion in 5 patients. Complete or near complete responses (CR + nCR) have been observed in 6 patients (33%), very good partial response and partial response (VGPR + PR) in 4 patients (22%) and minor response in 5 patients (28%) for an overall response (CR, nCR, VGPR, PR, MR) of 83%. One patient achieved stable disease and two progressed (11%). Of the 14 patients who achieved response, 8 continue treatment, 3 are in remission off therapy (2 in nCR and 1 in PR), 2 relapsed, and 1 died of pneumonitis during therapy. Grade 3 and 4 toxicities were mostly related to cytopenias (thrombocytopenia in 7 patients, neutropenia in 7 patients, pneumonitis in 5 patients) and occurred among patients who had baseline cytopenia at study entry. The most common grade 1 and 2 toxicities included fatigue, neuropathy, diarrhea, neutropenia, and thrombocytopenia. Conclusion: VDD combination shows promising overall activity and rate of CR and nCR and appears well tolerated. Based on these preliminary results, we have activated frontline VDD trial with 6 patients enrolled to date.
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combination therapy with Velcade doxil and dexamethasone vdd for patients with relapsed refractory multiple myeloma mm
Blood, 2005Co-Authors: Andrzej Jakubowiak, Lindsey Brackett, Tara Kendall, Judah Friedman, Mark S. KaminskiAbstract:Background: Combination regimens with Velcade demonstrate high activity in both relapsed/refractory and newly diagnosed MM, including higher than previously observed rates of complete responses (CR) and near complete responses (nCR). In this study, we evaluated the activity of a combination of Velcade, Doxil, and Dexamethasone (VDD) in relapsed/refractory MM. The rationale for combining these 3 agents was provided in pre-clinical studies which showed that Velcade can synergize with DNA-damaging agents via caspase-8 pathway and with Dexamethasone via caspase-9 pathway. In addition, prior clinical studies showed that combinations of Velcade with either Doxil or dexamethasone are well tolerated and more active than Velcade alone. The primary objective of the study was to assess the overall response to VDD and to estimate whether this combination can improve the rate of CR and nCR. Methods: The trial opened in November 2004 with target accrual of 30 patients. EBMT criteria were used for evaluation of response and nCR was defined as M-protein reduced to a level detectable by only immunofixation. The regimen in both relapsed/refractory and frontline trials was given as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and Dexamethasone at 40 mg orally on days 1–4. VDD was repeated every 3 weeks for a total of 6 cycles. After the completion of 6 cycles, patients in the relapsed/refractory trial were maintained on Velcade weekly and Dexamethasone on days 1–4 in 5-week cycles. Results: To date, 20 pts have been enrolled, 18 of whom are presently evaluable for response after receiving a mean of 3.6 cycles (range 1–6). The characteristics of the evaluable patients included the following: median age 62 (range 39–78), 1–5 prior lines of therapy, single autologous stem cell transplant in 14 patients, tandem transplant in 1 patient, allogeneic transplant in 1 patient, chromosome 13 deletion in 5 patients. Complete or near complete responses (CR + nCR) have been observed in 6 patients (33%), very good partial response and partial response (VGPR + PR) in 4 patients (22%) and minor response in 5 patients (28%) for an overall response (CR, nCR, VGPR, PR, MR) of 83%. One patient achieved stable disease and two progressed (11%). Of the 14 patients who achieved response, 8 continue treatment, 3 are in remission off therapy (2 in nCR and 1 in PR), 2 relapsed, and 1 died of pneumonitis during therapy. Grade 3 and 4 toxicities were mostly related to cytopenias (thrombocytopenia in 7 patients, neutropenia in 7 patients, pneumonitis in 5 patients) and occurred among patients who had baseline cytopenia at study entry. The most common grade 1 and 2 toxicities included fatigue, neuropathy, diarrhea, neutropenia, and thrombocytopenia. Conclusion: VDD combination shows promising overall activity and rate of CR and nCR and appears well tolerated. Based on these preliminary results, we have activated frontline VDD trial with 6 patients enrolled to date.
