A Phase I and Pharmacologic Trial of Two Schedules of the Proteasome Inhibitor, PS-341 (Bortezomib, Velcade), in Patients with Advanced Cancer

Dy, Grace K.; Thomas, James P.; Wilding, George; Bruzek, Laura M.; Mandrekar, Sumithra J.; Erlichman, Charles; Alberti, Dona; Binger, Kimberly; Pitot, Henry C.; Alberts, Steven R.; Hanson, Lorelei J.; Marnocha, Rebecca; Tutsch, Kendra D.; Kaufmann, Scott H.; Adjei, Alex A.

doi:10.1158/1078-0432.ccr-04-2068

Cited by 62 publications

(33 citation statements)

References 12 publications

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“…55 Contrary to our initial expectations, bortezomib did not produce a disproportionately adverse effect or enhance ␣-globin accumulation in ␤-thalassemic mice. This may be explained by our observations that multiple erythroid PQC pathways are activated additively by ␤-thalassemia and systemic protease inhibition.…”

Section: Discussioncontrasting

confidence: 83%

Integrated protein quality-control pathways regulate free α-globin in murine β-thalassemia

Khandros

Thom

D'Souza

et al. 2012

Blood

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Cells remove unstable polypeptides through protein quality-control (PQC) pathways such as ubiquitin-mediated proteolysis and autophagy. In the present study, we investigated how these pathways are used in ␤-thalassemia, a common hemoglobinopathy in which ␤-globin gene mutations cause the accumulation and precipitation of cytotoxic ␣-globin subunits. In ␤-thalassemic erythrocyte precursors, free ␣-globin was polyubiquitinated and degraded by the proteasome. These cells exhibited enhanced proteasome activity, and transcriptional profiling revealed coordinated induction of most proteasome subunits that was mediated by the stress-response transcription factor Nrf1. In isolated thalassemic cells, short-term proteasome inhibition blocked the degradation of free ␣-globin. In contrast, prolonged in vivo treatment of ␤-thalassemic mice with the proteasome inhibitor bortezomib did not enhance the accumulation of free ␣-globin. Rather, systemic proteasome inhibition activated compensatory proteotoxic stress-response mechanisms, including autophagy, which cooperated with ubiquitin-mediated proteolysis to degrade free ␣-globin in erythroid cells. Our findings show that multiple interregulated PQC responses degrade excess ␣-globin. Therefore, ␤-thalassemia fits into the broader framework of protein-aggregation disorders that use PQC pathways as cellprotective mechanisms. (Blood. 2012; 119(22):5265-5275) IntroductionThe production of functional hemoglobin A (HbA) tetramers (␣ 2 ␤ 2 ) requires the coordinated synthesis and assembly of ␣-and ␤-globin protein chains and iron-containing heme groups. Individually, all HbA components are toxic to RBCs and their precursors, as illustrated by ␤-thalassemias, a common hemoglobinopathy in which ␤-globin gene (HBB) mutations cause the buildup of free ␣-globin. 1 These unpaired ␣ chains initiate an oxidative damage cascade and form damaging precipitates that contribute largely to the clinical problems associated with ␤-thalassemia.The pathophysiology of ␤-thalassemia bears similarities to a diverse group of protein-aggregation diseases affecting multiple organs (for review, see Khandros and Weiss 2 ). These disorders, which include Parkinson disease, Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, and ␣ 1 -antitrypsin deficiency, are caused by the accumulation of unstable, relatively insoluble proteins. It is believed that the affected cells can detoxify and remove these damaging proteins via multiple interacting biochemical pathways called protein quality-control (PQC) pathways, but that disease ensues when such compensatory mechanisms are overwhelmed (for review, see Ciechanover and Brundin,3 Ding and Yin, 4 and Jaeger and Wyss-Coray 5 ). Cellular PQC systems include molecular chaperones, ubiquitin-mediated proteolysis, and autophagy. Several lines of evidence suggest that ␤-thalassemic erythroid cells use PQC pathways to detoxify free ␣-globin (for review, see Khandros and Weiss 2 ): (1) the clinical severity of ␤-thalassemia is proportional to the degree of ␣-glo...

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Section: Discussioncontrasting

confidence: 83%

Integrated protein quality-control pathways regulate free α-globin in murine β-thalassemia

Khandros

Thom

D'Souza

et al. 2012

Blood

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“…The DLTs were bone pain and febrile neutropenia. The bortezomib dose was slightly higher than the approved 1.3 mg m À2 on the same schedule, but similar to that identified in phase I studies evaluating single-agent bortezomib administered on the same schedule (Aghajanian et al, 2002;Dy et al, 2005). Slightly higher doses were tolerated when bortezomib was administered weekly (Papandreou et al, 2004) or on days 1 and 4 every 14 days (Hamilton et al, 2005).…”

Section: Discussionsupporting

confidence: 59%

Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study

et al. 2008

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The aim of this study was to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of bortezomib plus docetaxel in patients with anthracycline-pretreated advanced/metastatic breast cancer. Forty-eight patients received up to eight 21-day cycles of docetaxel (60 -100 mg m À2 on day 1) plus bortezomib (1.0 -1.5 mg m À2 on days 1, 4, 8, and 11). Pharmacodynamic and pharmacokinetic analyses were performed in a subset of patients. Five patients experienced DLTs: grade 3 bone pain (n ¼ 1) and febrile neutropenia (n ¼ 4). The MTD was bortezomib 1.5 mg m À2 plus docetaxel 75 mg m À2 . All 48 patients were assessable for safety and efficacy. The most common adverse events were diarrhoea, nausea, alopecia, asthenia, and vomiting. The most common grade 3/4 toxicities were neutropenia (44%), and febrile neutropenia and diarrhoea (each 19%). Overall patient response rate was 29%. Median time to progression was 5.4 months. In patients with confirmed response, median time to response was 1.3 months and median duration of response was 3.2 months. At the MTD, response rate was 38%. Pharmacokinetic characteristics of bortezomib/ docetaxel were comparable with single-agent data. Addition of docetaxel appeared not to affect bortezomib inhibition of 20S proteasome activity. Mean alpha-1 acid glycoprotein concentrations increased from baseline at nearly all time points across different bortezomib dose levels. Bortezomib plus docetaxel is an active combination for anthracycline-pretreated advanced/metastatic breast cancer. The safety profile is manageable and consistent with the side effects of the individual agents.

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“…Parthenolide, which could activate the IKK pathway and subsequent inhibit NF-κB and its downstream antiapoptotic proteins, was tested in the main human NSCLC cell lines. In addition, previous data support the hypothesis that combining mechanistically similar drugs, which share at least one target, is a viable strategy that can result in a greater than additive therapeutic benefit (45)(46)(47)(48). Further studies are in progress in our laboratory to delineate the role of these proteins in the execution of the synergistic effect by Taxol and parthenolide.…”

Section: Parthenolide Potentiates Chemosensitizationmentioning

confidence: 68%

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

Zhang

Qiu²,

Jin³

et al. 2009

Molecular Cancer Research

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In this study, we have examined the molecular events induced by parthenolide, a sesquiterpene lactone, and explored possible mechanisms of resistance and sensitization of tumor cells to Taxol. We showed that parthenolide could antagonize Taxol-mediated nuclear factor-κB (NF-κB) nuclear translocation and activation and Bcl-xl up-regulation by selectively targeting I-κB kinase activity. In A549 cells, inhibition of nuclear factor-κB by parthenolide resulted in activation of the mitochondrial death pathway to promote cytochrome c release and caspase 3 and 9 activation. In contrast, Taxol alone induced apoptosis via a pathway independent of mitochondria cytochrome c cascade. In addition, depletion of Bcl-xl rescued the apoptotic response to Taxol. Moreover, treatment with parthenolide increased the efficacy of the Taxol-induced inhibition of A549 tumor xenografts in mice. This study elucidated the cellular responses induced by parthenolide that decrease the threshold of mitochodriadependent apoptosis in the treatment of non-small cell lung cancer cells.

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A Phase I and Pharmacologic Trial of Two Schedules of the Proteasome Inhibitor, PS-341 (Bortezomib, Velcade), in Patients with Advanced Cancer

Cited by 62 publications

References 12 publications

Integrated protein quality-control pathways regulate free α-globin in murine β-thalassemia

Integrated protein quality-control pathways regulate free α-globin in murine β-thalassemia

Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

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