Proteasome Inhibitors in Cancer Therapy: Lessons from the First Decade

Orłowski, Robert Z.; Kuhn, Deborah J.

doi:10.1158/1078-0432.ccr-07-2218

Cited by 527 publications

(504 citation statements)

References 115 publications

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“…5) In addition to the treatment of relapsed or refractory multiple myeloma, bortezomib is also undergoing clinical trials for the treatment of several cancers (e.g., prostate). 20) TP-110 ( Fig.…”

Section: Discussionmentioning

confidence: 99%

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Increased ABCB1 Expression in TP-110-Resistant RPMI-8226 Cells

Iijima

Momose

Ikeda

2010

Bioscience, Biotechnology, and Biochemistry

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, a novel proteasome inhibitor, has been found to possess potent growth inhibition in human multiple myeloma cells. To enhance its therapeutic effects, we established TP-110-resistant RPMI-8226 (RPMI-8226/ TP-110) cells and elucidated their resistance mechanisms. The IC 50 value for TP-110 cytotoxicity in the RPMI-8226/TP-110 cells was about 10-fold higher than that of the parental sensitive cells. The RPMI-8226/TP-110 cells exhibited distinct drug resistance to other proteasome inhibitors. Furthermore, they showed high cross-resistance to the cytotoxic effects of doxorubicin, etoposide, taxol, and vincristine. P-glycoprotein (MDR1), encoded by ABCB1, was elevated in the RPMI-8226/TP-110 cells, and the MDR1 inhibitor verapamil overcame their resistance to TP-110. The results of DNA microarray and RT-PCR suggested that the expression of ABCB1 is significantly elevated in RPMI-8226/TP-110 cells. This indicates that resistance in RPMI-8226/TP-110 cells is involved in the expression of P-glycoprotein, a drug-efflux pump.

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Section: Discussionmentioning

confidence: 99%

“…[3][4][5] Bortezomib, a dipeptide boronic acid, shows significant anti-tumor activity in multiple myeloma cells. In 2003, the U.S. Food and Drug Administration (FDA) approved bortezomib (VELCADEÔ), formerly known as PS-341, for the treatment of relapsed/ refractory multiple myeloma.…”

mentioning

confidence: 99%

Increased ABCB1 Expression in TP-110-Resistant RPMI-8226 Cells

Iijima

Momose

Ikeda

2010

Bioscience, Biotechnology, and Biochemistry

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“…However, we believe that this dual specificity may be exploited to target at the same time two relevant pathways for cancer onset and progression (69,70). Interestingly, the association of γ-secretase inhibitors with chemotherapy has been proposed very recently as a novel approach for the treatment of metastatic colon cancer (71), whereas the use of proteasome inhibitors into the clinic dates back of a decade and now is part of the standard treatment of some hematologic malignancies (72). Although a molecule having dual specificity may be associated to a higher toxicity with respect to more specific inhibitors, it may have the advantage of a later onset of drug resistance due to the possibility of targeting efficiently two targets (72,73).…”

Section: Discussionmentioning

confidence: 99%

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Monticone

Biollo

Fabiano

et al. 2009

Molecular Cancer Research

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γ-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. Here, we investigated two of such inhibitors, the Benzyloxicarbonyl-Leu-Leu-Nle-CHO (LLNle) and the N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to assess whether they were effective in killing human glioblastoma tumor-initiating cells (GBM TIC) in vitro. We found that only LLNle was able at the micromolar range to induce the death of GBM TICs by apoptosis. To determine the cellular processes that were activated in GBM TICs by treatment with LLNle, we analyzed the amount of the NOTCH intracellular domain and the gene expression profiles following treatment with LLNle, DAPT, and DMSO (vehicle). We found that LLNIe, beside inhibiting the generation of the NOTCH intracellular domain, also induces proteasome inhibition, proteolytic stress, and mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activating genes acting as mitotic inhibitors. DNA content flow cytometry clearly showed that cells treated with LLNle undergo arrest in the G 2 -M phases of the cell cycle. We also found that DAPT and L-685,458, another selective Notch inhibitor, were unable to kill GBM TICs, whereas lactacystin, a pure proteasome inhibitor, was effective although at a much less extent than LLNle. These data show that LLNle kills GBM TIC cells by inhibiting the proteasome activity. We suggest that LLNle, being able to target two relevant pathways for GBM TIC survival, may have a potential therapeutic value that deserves further investigation in animal models.

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“…Increased expression of E3 ligases also reportedly is correlated with chemoresistance and a poor prognosis in patients with cancer. 14,15 Thus, E3 ubiquitin ligases have been considered as potential cancer drug targets and prognostic biomarkers. [16][17][18][19] p53-Induced RING-H2 protein (PIRH2) is a newly identified E3 ubiquitin ligase that promotes p53 degradation.…”

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p53‐induced RING‐H2 protein, a novel marker for poor survival in hepatocellular carcinoma after hepatic resection

Wang

Yang

Guo

et al. 2009

Cancer

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Novel copolyacrylates containing various molar ratios of 5,10,15‐tri[p‐(9‐methoxy‐triethylenoxy)phenyl]‐20‐(p‐acryloxyphenyl)porphyrin units in the chains have been synthesized, and their chemical structure was determined by NMR and MALDI‐TOF mass spectrometry. Sensing response of the synthesized copolymers has been tested for trifluoroacetic and hydrochloric acids and nitrogen dioxide analytes. The reported sensing data indicate that porphyrin units are interacting with analytes in a reversible fashion. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011

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Proteasome Inhibitors in Cancer Therapy: Lessons from the First Decade

Abstract: The ubiquitin-proteasome pathway is involved in intracellular protein turnover, and its function is crucial to cellular homeostasis.

Cited by 527 publications

References 115 publications

Increased ABCB1 Expression in TP-110-Resistant RPMI-8226 Cells

Increased ABCB1 Expression in TP-110-Resistant RPMI-8226 Cells

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

p53‐induced RING‐H2 protein, a novel marker for poor survival in hepatocellular carcinoma after hepatic resection

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