Dual inhibition of canonical and noncanonical NF-κB pathways demonstrates significant antitumor activities in multiple myeloma

Claire Fabre, Naoya Mimura, Kathryn Bobb, Sun Young Kong, Gullu Gorgun, Diana Cirstea, Yiguo Hu, Jiro Minami, Hiroto Ohguchi, Jie Zhang, Jeffrey Meshulam, Ruben D. Carrasco, Yu Tzu Tai, Paul G. Richardson, Teru Hideshima, Kenneth C. Anderson

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Purpose: NF-κB transcription factor plays a key role in the pathogenesis of multiple myeloma in the context of the bone marrow microenvironment. Both canonical and noncanonical pathways contribute to total NF-κB activity. Recent studies have shown a critical role for the noncanonical pathway: selective inhibitors of the canonical pathway present a limited activity, mutations of the noncanonical pathway are frequent, and bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity. Experimental Design: Multiple myeloma cell lines, primary patient cells, and the human multiple myeloma xenograft murine model were used to examine the biologic impact of dual inhibition of both canonical and noncanonical NF-κB pathways. Results: We show that PBS-1086 induces potent cytotoxicity in multiple myeloma cells but not in peripheral blood mononuclear cells. PBS-1086 overcomes the proliferative and antiapoptotic effects of the bone marrow milieu, associated with inhibition of NF-κB activity. Moreover, PBS-1086 strongly enhances the cytotoxicity of bortezomib in bortezomib-resistant multiple myeloma cell lines and patient multiple myeloma cells. PBS-1086 also inhibits osteoclastogenesis through an inhibition of RANK ligand (RANKL)-induced NF-κB activation. Finally, in a xenograft model of human multiple myeloma in the bone marrow milieu, PBS-1086 shows significant in vivo anti-multiple myeloma activity and prolongs host survival, associated with apoptosis and inhibition of both NF-κB pathways in tumor cells. Conclusions: Our data show that PBS-1086 is a promising dual inhibitor of the canonical and noncanonical NF-κB pathways. Our preclinical study therefore provides the framework for clinical evaluation of PBS-1086 in combination with bortezomib for the treatment of multiple myeloma and related bone lesions.

Original languageEnglish (US)
Pages (from-to)4669-4681
Number of pages13
JournalClinical Cancer Research
Volume18
Issue number17
DOIs
StatePublished - Sep 1 2012
Externally publishedYes

Fingerprint

Multiple Myeloma
Bone Marrow
Heterografts
RANK Ligand
Cell Line
PBS-1086
Osteogenesis
Blood Cells
Research Design
Transcription Factors
Apoptosis
Bone and Bones
Mutation
Survival
Bortezomib

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dual inhibition of canonical and noncanonical NF-κB pathways demonstrates significant antitumor activities in multiple myeloma. / Fabre, Claire; Mimura, Naoya; Bobb, Kathryn; Kong, Sun Young; Gorgun, Gullu; Cirstea, Diana; Hu, Yiguo; Minami, Jiro; Ohguchi, Hiroto; Zhang, Jie; Meshulam, Jeffrey; Carrasco, Ruben D.; Tai, Yu Tzu; Richardson, Paul G.; Hideshima, Teru; Anderson, Kenneth C.

In: Clinical Cancer Research, Vol. 18, No. 17, 01.09.2012, p. 4669-4681.

Research output: Contribution to journalArticle

Fabre, C, Mimura, N, Bobb, K, Kong, SY, Gorgun, G, Cirstea, D, Hu, Y, Minami, J, Ohguchi, H, Zhang, J, Meshulam, J, Carrasco, RD, Tai, YT, Richardson, PG, Hideshima, T & Anderson, KC 2012, 'Dual inhibition of canonical and noncanonical NF-κB pathways demonstrates significant antitumor activities in multiple myeloma', Clinical Cancer Research, vol. 18, no. 17, pp. 4669-4681. https://doi.org/10.1158/1078-0432.CCR-12-0779
Fabre, Claire ; Mimura, Naoya ; Bobb, Kathryn ; Kong, Sun Young ; Gorgun, Gullu ; Cirstea, Diana ; Hu, Yiguo ; Minami, Jiro ; Ohguchi, Hiroto ; Zhang, Jie ; Meshulam, Jeffrey ; Carrasco, Ruben D. ; Tai, Yu Tzu ; Richardson, Paul G. ; Hideshima, Teru ; Anderson, Kenneth C. / Dual inhibition of canonical and noncanonical NF-κB pathways demonstrates significant antitumor activities in multiple myeloma. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 17. pp. 4669-4681.
@article{3659c5f39f2e4a258e56fb31b2365a29,
title = "Dual inhibition of canonical and noncanonical NF-κB pathways demonstrates significant antitumor activities in multiple myeloma",
abstract = "Purpose: NF-κB transcription factor plays a key role in the pathogenesis of multiple myeloma in the context of the bone marrow microenvironment. Both canonical and noncanonical pathways contribute to total NF-κB activity. Recent studies have shown a critical role for the noncanonical pathway: selective inhibitors of the canonical pathway present a limited activity, mutations of the noncanonical pathway are frequent, and bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity. Experimental Design: Multiple myeloma cell lines, primary patient cells, and the human multiple myeloma xenograft murine model were used to examine the biologic impact of dual inhibition of both canonical and noncanonical NF-κB pathways. Results: We show that PBS-1086 induces potent cytotoxicity in multiple myeloma cells but not in peripheral blood mononuclear cells. PBS-1086 overcomes the proliferative and antiapoptotic effects of the bone marrow milieu, associated with inhibition of NF-κB activity. Moreover, PBS-1086 strongly enhances the cytotoxicity of bortezomib in bortezomib-resistant multiple myeloma cell lines and patient multiple myeloma cells. PBS-1086 also inhibits osteoclastogenesis through an inhibition of RANK ligand (RANKL)-induced NF-κB activation. Finally, in a xenograft model of human multiple myeloma in the bone marrow milieu, PBS-1086 shows significant in vivo anti-multiple myeloma activity and prolongs host survival, associated with apoptosis and inhibition of both NF-κB pathways in tumor cells. Conclusions: Our data show that PBS-1086 is a promising dual inhibitor of the canonical and noncanonical NF-κB pathways. Our preclinical study therefore provides the framework for clinical evaluation of PBS-1086 in combination with bortezomib for the treatment of multiple myeloma and related bone lesions.",
author = "Claire Fabre and Naoya Mimura and Kathryn Bobb and Kong, {Sun Young} and Gullu Gorgun and Diana Cirstea and Yiguo Hu and Jiro Minami and Hiroto Ohguchi and Jie Zhang and Jeffrey Meshulam and Carrasco, {Ruben D.} and Tai, {Yu Tzu} and Richardson, {Paul G.} and Teru Hideshima and Anderson, {Kenneth C.}",
year = "2012",
month = "9",
day = "1",
doi = "10.1158/1078-0432.CCR-12-0779",
language = "English (US)",
volume = "18",
pages = "4669--4681",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "17",

}

TY - JOUR

T1 - Dual inhibition of canonical and noncanonical NF-κB pathways demonstrates significant antitumor activities in multiple myeloma

AU - Fabre, Claire

AU - Mimura, Naoya

AU - Bobb, Kathryn

AU - Kong, Sun Young

AU - Gorgun, Gullu

AU - Cirstea, Diana

AU - Hu, Yiguo

AU - Minami, Jiro

AU - Ohguchi, Hiroto

AU - Zhang, Jie

AU - Meshulam, Jeffrey

AU - Carrasco, Ruben D.

AU - Tai, Yu Tzu

AU - Richardson, Paul G.

AU - Hideshima, Teru

AU - Anderson, Kenneth C.

PY - 2012/9/1

Y1 - 2012/9/1

N2 - Purpose: NF-κB transcription factor plays a key role in the pathogenesis of multiple myeloma in the context of the bone marrow microenvironment. Both canonical and noncanonical pathways contribute to total NF-κB activity. Recent studies have shown a critical role for the noncanonical pathway: selective inhibitors of the canonical pathway present a limited activity, mutations of the noncanonical pathway are frequent, and bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity. Experimental Design: Multiple myeloma cell lines, primary patient cells, and the human multiple myeloma xenograft murine model were used to examine the biologic impact of dual inhibition of both canonical and noncanonical NF-κB pathways. Results: We show that PBS-1086 induces potent cytotoxicity in multiple myeloma cells but not in peripheral blood mononuclear cells. PBS-1086 overcomes the proliferative and antiapoptotic effects of the bone marrow milieu, associated with inhibition of NF-κB activity. Moreover, PBS-1086 strongly enhances the cytotoxicity of bortezomib in bortezomib-resistant multiple myeloma cell lines and patient multiple myeloma cells. PBS-1086 also inhibits osteoclastogenesis through an inhibition of RANK ligand (RANKL)-induced NF-κB activation. Finally, in a xenograft model of human multiple myeloma in the bone marrow milieu, PBS-1086 shows significant in vivo anti-multiple myeloma activity and prolongs host survival, associated with apoptosis and inhibition of both NF-κB pathways in tumor cells. Conclusions: Our data show that PBS-1086 is a promising dual inhibitor of the canonical and noncanonical NF-κB pathways. Our preclinical study therefore provides the framework for clinical evaluation of PBS-1086 in combination with bortezomib for the treatment of multiple myeloma and related bone lesions.

AB - Purpose: NF-κB transcription factor plays a key role in the pathogenesis of multiple myeloma in the context of the bone marrow microenvironment. Both canonical and noncanonical pathways contribute to total NF-κB activity. Recent studies have shown a critical role for the noncanonical pathway: selective inhibitors of the canonical pathway present a limited activity, mutations of the noncanonical pathway are frequent, and bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity. Experimental Design: Multiple myeloma cell lines, primary patient cells, and the human multiple myeloma xenograft murine model were used to examine the biologic impact of dual inhibition of both canonical and noncanonical NF-κB pathways. Results: We show that PBS-1086 induces potent cytotoxicity in multiple myeloma cells but not in peripheral blood mononuclear cells. PBS-1086 overcomes the proliferative and antiapoptotic effects of the bone marrow milieu, associated with inhibition of NF-κB activity. Moreover, PBS-1086 strongly enhances the cytotoxicity of bortezomib in bortezomib-resistant multiple myeloma cell lines and patient multiple myeloma cells. PBS-1086 also inhibits osteoclastogenesis through an inhibition of RANK ligand (RANKL)-induced NF-κB activation. Finally, in a xenograft model of human multiple myeloma in the bone marrow milieu, PBS-1086 shows significant in vivo anti-multiple myeloma activity and prolongs host survival, associated with apoptosis and inhibition of both NF-κB pathways in tumor cells. Conclusions: Our data show that PBS-1086 is a promising dual inhibitor of the canonical and noncanonical NF-κB pathways. Our preclinical study therefore provides the framework for clinical evaluation of PBS-1086 in combination with bortezomib for the treatment of multiple myeloma and related bone lesions.

UR - http://www.scopus.com/inward/record.url?scp=84865736407&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865736407&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-12-0779

DO - 10.1158/1078-0432.CCR-12-0779

M3 - Article

C2 - 22806876

AN - SCOPUS:84865736407

VL - 18

SP - 4669

EP - 4681

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 17

ER -