Potent and selective inhibitors of the proteasome: Dipeptidyl boronic acids

Adams, Julian; Behnke, Mark L.; Chen, Shaowu; Cruickshank, Amy; Dick, Lawrence R.; Grenier, Louis; Klunder, Janice M.; Ma, Yuting; Plamondon, Louis; Stein, Ross L.

doi:10.1016/s0960-894x(98)00029-8

Cited by 656 publications

(482 citation statements)

References 19 publications

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“…Bortezomib (PS-341/ Velcade) is a dipeptide boronic acid inhibitor that is highly selective for the proteasome, having little affinity for other proteases ( Figure 1A). Bortezomib forms a covalent bond with the active site threonine in the core of the 20S proteasome, and inhibits the chymotryptic activity of the proteasome (17). In 2003, bortezomib was approved in the United States for the treatment of relapsed and refractory multiple myeloma (18).…”

Section: Introductionmentioning

confidence: 99%

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Congdon

Pourpak

Escalante

et al. 2008

Biochemical Pharmacology

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Multiple myeloma (MM) is an incurable malignancy of plasma cells. Although multiple myeloma patients often respond to initial therapy, the majority of patients will relapse with disease that is refractory to further drug treatment. Thus, new therapeutic strategies are needed. One common mechanism of acquired drug resistance involves a reduction in the expression or function of the drug target. We hypothesized that the cytotoxic activity of topoisomerase II (topo II) poisons could be enhanced, and drug resistance overcome, by increasing the expression and activity of the drug target, topo II in myeloma cells. To test this hypothesis, we evaluated the cytotoxicity of the anthracenecontaining topo II poison, ethonafide (AMP-53/6-ethoxyazonafide), in combination with the proteasome inhibitor bortezomib (PS-341/Velcade). Combination drug activity studies were done in 8226/S myeloma cells and its drug resistant subclone, 8226/Dox1V. We found that a 24-hour treatment of cells with bortezomib maximally increased topo IIα protein expression and activity, and consistently increased the cytotoxicity of ethonafide in the 8226/S and 8226/Dox1V cell lines. This increase in cytotoxicity corresponded to an increase in DNA double-strand breaks, as measured by the neutral comet assay. Therefore, increasing topo IIα expression through inhibition of proteasomal degradation increased DNA double-strand breaks and enhanced the cytotoxicity of the topo II poison ethonafide. These data suggest that bortezomib-mediated stabilization of topo IIα expression may potentiate the cytotoxic activity of topo II poisons and thereby, provide a strategy to circumvent drug resistance.

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Section: Introductionmentioning

confidence: 99%

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Congdon

Pourpak

Escalante

et al. 2008

Biochemical Pharmacology

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“…16 Compared with peptide aldehyde analogs, dipeptidyl boronic acids are much more potent and dissociate more slowly from the proteasome, inducing stable proteasome inhibition. 3,17 Among peptide boronic acids, the small molecule PS-341 or bortezomib, as a single agent was found to have potent cytotoxicity in a standard National Cancer Institute in vitro screening of 60 cell lines derived from multiple human tumors. 18 Owing to its selectivity, reversible interaction with the proteasome, favorable pharmacokinetics and ease of synthesis, PS-341 has been the first proteasome inhibitor to reach clinical trials in cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Proteasome inhibitor bortezomib for the treatment of multiple myeloma

2006

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“…[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.…”

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confidence: 99%

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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Potent and selective inhibitors of the proteasome: Dipeptidyl boronic acids

Cited by 656 publications

References 19 publications

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Proteasome inhibitor bortezomib for the treatment of multiple myeloma

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

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