The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP

Thomas J. Sayers, Alan D. Brooks, Crystal Y. Koh, Weihong Ma, Naoko Seki, Arati Raziuddin, Bruce R. Blazar, Xia Zhang, Peter J. Elliott, William J. Murphy

Research output: Contribution to journalArticle

203 Citations (Scopus)

Abstract

Because of the pivotal role the proteasome plays in apoptosis, inhibitors of this enzyme, such as PS-341, provide a great opportunity for exploring synergy between proteasome inhibition and other apoptosis-inducing agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in tumor cells. In overnight assays, combinations of PS-341 and TRAIL were much more effective than either agent alone in promoting apoptosis of a murine myeloid leukemia, C1498, and a murine renal cancer, Renca. For C1498 cells, apoptosis sensitization by PS-341 affected neither the activity of nuclear factor KB (NF-κB) nor the levels of most antiapoptotic proteins. However, reductions in the antiapoptotic protein c-FLIP in response to PS-341 were observed in both C1498 and Renca cells. Treatment of normal bone marrow mixed with C1498 tumor cells for 18 hours with a combination of PS-341 and TRAIL resulted in a specific depletion of the tumor cells. Upon transfer to irradiated syngeneic recipient mice, mixtures treated with the PS-341 plus TRAIL combination resulted in enhanced long-term tumor-free survival of mice. These data therefore support the targeting of apoptotic pathways in tumor cells, using combinations of agents such as PS-341 and TRAIL that interact synergistically to preferentially promote tumor cell apoptosis.

Original languageEnglish
Pages (from-to)303-310
Number of pages8
JournalBlood
Volume102
Issue number1
DOIs
Publication statusPublished - Jul 1 2003

Fingerprint

Proteasome Inhibitors
Tumors
Apoptosis
Cells
Neoplasms
Proteasome Endopeptidase Complex
Myeloid Leukemia
Kidney Neoplasms
Enzyme Inhibitors
Bortezomib
Assays
Bone
Proteins
Tumor Necrosis Factor-alpha
Bone Marrow
Ligands

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. / Sayers, Thomas J.; Brooks, Alan D.; Koh, Crystal Y.; Ma, Weihong; Seki, Naoko; Raziuddin, Arati; Blazar, Bruce R.; Zhang, Xia; Elliott, Peter J.; Murphy, William J.

In: Blood, Vol. 102, No. 1, 01.07.2003, p. 303-310.

Research output: Contribution to journalArticle

Sayers, TJ, Brooks, AD, Koh, CY, Ma, W, Seki, N, Raziuddin, A, Blazar, BR, Zhang, X, Elliott, PJ & Murphy, WJ 2003, 'The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP', Blood, vol. 102, no. 1, pp. 303-310. https://doi.org/10.1182/blood-2002-09-2975
Sayers, Thomas J. ; Brooks, Alan D. ; Koh, Crystal Y. ; Ma, Weihong ; Seki, Naoko ; Raziuddin, Arati ; Blazar, Bruce R. ; Zhang, Xia ; Elliott, Peter J. ; Murphy, William J. / The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. In: Blood. 2003 ; Vol. 102, No. 1. pp. 303-310.
@article{50d3bf9eac274855aaf6e891db635e23,
title = "The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP",
abstract = "Because of the pivotal role the proteasome plays in apoptosis, inhibitors of this enzyme, such as PS-341, provide a great opportunity for exploring synergy between proteasome inhibition and other apoptosis-inducing agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in tumor cells. In overnight assays, combinations of PS-341 and TRAIL were much more effective than either agent alone in promoting apoptosis of a murine myeloid leukemia, C1498, and a murine renal cancer, Renca. For C1498 cells, apoptosis sensitization by PS-341 affected neither the activity of nuclear factor KB (NF-κB) nor the levels of most antiapoptotic proteins. However, reductions in the antiapoptotic protein c-FLIP in response to PS-341 were observed in both C1498 and Renca cells. Treatment of normal bone marrow mixed with C1498 tumor cells for 18 hours with a combination of PS-341 and TRAIL resulted in a specific depletion of the tumor cells. Upon transfer to irradiated syngeneic recipient mice, mixtures treated with the PS-341 plus TRAIL combination resulted in enhanced long-term tumor-free survival of mice. These data therefore support the targeting of apoptotic pathways in tumor cells, using combinations of agents such as PS-341 and TRAIL that interact synergistically to preferentially promote tumor cell apoptosis.",
author = "Sayers, {Thomas J.} and Brooks, {Alan D.} and Koh, {Crystal Y.} and Weihong Ma and Naoko Seki and Arati Raziuddin and Blazar, {Bruce R.} and Xia Zhang and Elliott, {Peter J.} and Murphy, {William J.}",
year = "2003",
month = "7",
day = "1",
doi = "10.1182/blood-2002-09-2975",
language = "English",
volume = "102",
pages = "303--310",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "1",

}

TY - JOUR

T1 - The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP

AU - Sayers, Thomas J.

AU - Brooks, Alan D.

AU - Koh, Crystal Y.

AU - Ma, Weihong

AU - Seki, Naoko

AU - Raziuddin, Arati

AU - Blazar, Bruce R.

AU - Zhang, Xia

AU - Elliott, Peter J.

AU - Murphy, William J.

PY - 2003/7/1

Y1 - 2003/7/1

N2 - Because of the pivotal role the proteasome plays in apoptosis, inhibitors of this enzyme, such as PS-341, provide a great opportunity for exploring synergy between proteasome inhibition and other apoptosis-inducing agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in tumor cells. In overnight assays, combinations of PS-341 and TRAIL were much more effective than either agent alone in promoting apoptosis of a murine myeloid leukemia, C1498, and a murine renal cancer, Renca. For C1498 cells, apoptosis sensitization by PS-341 affected neither the activity of nuclear factor KB (NF-κB) nor the levels of most antiapoptotic proteins. However, reductions in the antiapoptotic protein c-FLIP in response to PS-341 were observed in both C1498 and Renca cells. Treatment of normal bone marrow mixed with C1498 tumor cells for 18 hours with a combination of PS-341 and TRAIL resulted in a specific depletion of the tumor cells. Upon transfer to irradiated syngeneic recipient mice, mixtures treated with the PS-341 plus TRAIL combination resulted in enhanced long-term tumor-free survival of mice. These data therefore support the targeting of apoptotic pathways in tumor cells, using combinations of agents such as PS-341 and TRAIL that interact synergistically to preferentially promote tumor cell apoptosis.

AB - Because of the pivotal role the proteasome plays in apoptosis, inhibitors of this enzyme, such as PS-341, provide a great opportunity for exploring synergy between proteasome inhibition and other apoptosis-inducing agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in tumor cells. In overnight assays, combinations of PS-341 and TRAIL were much more effective than either agent alone in promoting apoptosis of a murine myeloid leukemia, C1498, and a murine renal cancer, Renca. For C1498 cells, apoptosis sensitization by PS-341 affected neither the activity of nuclear factor KB (NF-κB) nor the levels of most antiapoptotic proteins. However, reductions in the antiapoptotic protein c-FLIP in response to PS-341 were observed in both C1498 and Renca cells. Treatment of normal bone marrow mixed with C1498 tumor cells for 18 hours with a combination of PS-341 and TRAIL resulted in a specific depletion of the tumor cells. Upon transfer to irradiated syngeneic recipient mice, mixtures treated with the PS-341 plus TRAIL combination resulted in enhanced long-term tumor-free survival of mice. These data therefore support the targeting of apoptotic pathways in tumor cells, using combinations of agents such as PS-341 and TRAIL that interact synergistically to preferentially promote tumor cell apoptosis.

UR - http://www.scopus.com/inward/record.url?scp=0038240386&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038240386&partnerID=8YFLogxK

U2 - 10.1182/blood-2002-09-2975

DO - 10.1182/blood-2002-09-2975

M3 - Article

VL - 102

SP - 303

EP - 310

JO - Blood

JF - Blood

SN - 0006-4971

IS - 1

ER -