Activity of bortezomib, a proteasome inhibitor, in breast cancer cells: Association with negative estrogen receptor and IKK/NF-κB expression

Tapia, M.; Codony-Servat, Jordi; Domingo-Domenech, J.; Ferrer, Berta; Fernandez, P. L.; Ross, Jeff; Rolfe, Mark; Gascón, Pere; Rovira, Ana; Albanell, Joan

doi:10.1200/jco.2005.23.16_suppl.3169

Cited by 2 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IL-8 mRNA levels ( Fig 2C ) and cytokine release ( Fig 2D ) were significantly decreased in cells transfected with IL-8 specific siRNA compared to control siRNA. As previously observed [ 49 , 50 ], BZ decreased viability and proliferation of TNBC cells ( Fig 2E and 2F ). Importantly, IL-8 suppression significantly potentiated the BZ-mediated cytotoxic effect ( Fig 2E ).…”

Section: Resultssupporting

confidence: 89%

“…Since TNBC patients are unresponsive to current targeted therapies, new therapeutic strategies are vital. Although previous studies have shown that proteasome inhibition induces apoptosis in TNBC cells [ 49 , 50 ], suggesting a potential therapeutic activity in TNBC, clinical trials using PI as single agents have produced disappointing results. In this study, we demonstrate that proteasome inhibition induces expression of IL-8 and its receptors CXCR1 and CXCR2, resulting in increased survival, proliferation, and migration of TNBC cells.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Proteasome inhibition induces IKK-dependent interleukin-8 expression in triple negative breast cancer cells: Opportunity for combination therapy

et al. 2018

View full text Add to dashboard Cite

Triple negative breast cancer (TNBC) cells express increased levels of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8), which promotes their proliferation and migration. Because TNBC patients are unresponsive to current targeted therapies, new therapeutic strategies are urgently needed. While proteasome inhibition by bortezomib (BZ) or carfilzomib (CZ) has been effective in treating hematological malignancies, it has been less effective in solid tumors, including TNBC, but the mechanisms are incompletely understood. Here we report that proteasome inhibition significantly increases expression of IL-8, and its receptors CXCR1 and CXCR2, in TNBC cells. Suppression or neutralization of the BZ-induced IL-8 potentiates the BZ cytotoxic and anti-proliferative effect in TNBC cells. The IL-8 expression induced by proteasome inhibition in TNBC cells is mediated by IκB kinase (IKK), increased nuclear accumulation of p65 NFκB, and by IKK-dependent p65 recruitment to IL-8 promoter. Importantly, inhibition of IKK activity significantly decreases proliferation, migration, and invasion of BZ-treated TNBC cells. These data provide the first evidence demonstrating that proteasome inhibition increases the IL-8 signaling in TNBC cells, and suggesting that IKK inhibitors may increase effectiveness of proteasome inhibitors in treating TNBC.

show abstract

Section: Resultssupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Proteasome inhibition induces IKK-dependent interleukin-8 expression in triple negative breast cancer cells: Opportunity for combination therapy

et al. 2018

View full text Add to dashboard Cite

show abstract

“…estrogen-receptor-negative status plus a dysregulated IkBa/NF-kB system is associated with greater bortezomib antitumour activity (Tapia et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

View full text Add to dashboard Cite

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.

show abstract

Activity of bortezomib, a proteasome inhibitor, in breast cancer cells: Association with negative estrogen receptor and IKK/NF-κB expression

Cited by 2 publications

References 0 publications

Proteasome inhibition induces IKK-dependent interleukin-8 expression in triple negative breast cancer cells: Opportunity for combination therapy

Proteasome inhibition induces IKK-dependent interleukin-8 expression in triple negative breast cancer cells: Opportunity for combination therapy

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

Contact Info

Product

Resources

About