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Cited by 82Multiple Myeloma Research and TreatmentsNF-κB Signaling PathwaysSignaling Pathways in Disease

Dual Inhibition of Canonical and Noncanonical NF-κB Pathways Demonstrates Significant Antitumor Activities in Multiple Myeloma

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Fabre, Claire, Mimura, Naoya, Bobb, Kathryn, Kong, Sun-Young, Gorgun, Güllü, Cirstea, Diana, Hu, Yiguo, Minami, Jiro +8 more·2012·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-12-0779PMC PMC4456190

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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. Clin Cancer Res; 18(17); 4669–81. ©2012 AACR.

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  • Inhibitors specific to both canonical and non-canonical NF-κB pathways may offer more benefits for MM treatment.

    “Inhibitors specific to both canonical and non-canonical NF-κB pathways may offer more benefits for MM treatment [156].”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [156]

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Authors
Fabre, C., Mimura, N., Bobb, K., Kong, S.-Y., Gorgun, G., Cirstea, D., Hu, Y., Minami, J., Ohguchi, H., Zhang, J., Meshulam, J., Carrasco, R. D., Tai, Y.-T., Richardson, P. G., Hideshima, T., & Anderson, K. C.
Affiliations
  • Harvard University (US)
  • Authors' Affiliations: 1Jerome Lipper Multiple Myeloma Center, 2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; 3Profectus BioSciences Inc.; 4rel∼MD, Inc., Baltimore, Maryland; and 5Research Institute and Hospital, National Cancer Center, Korea
Corresponding author
Anderson, Kenneth C.
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2012-08-30
Volume
18
Issue
17
Pages
4669-4681
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-12-0779
PMC
PMC4456190
OpenAlex
W2138834974
Cited by
82
References
1
Citations by year
2026: 2 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 1 · 2021: 4 · 2020: 5 · 2019: 6 · 2018: 9 · 2017: 4 · 2016: 7 · 2015: 12 · 2014: 12 · 2013: 10 · 2012: 1
FWCI
7.45
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5p01ca078378-15)
  • National Cancer Institute (P01-CA078378, P50CA100707, R01CA050947)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
multiple myeloma, NF-κB signaling, canonical NF-κB pathway, non-canonical NF-κB signaling, bortezomib resistance, combination therapy, bone marrow microenvironment, osteoclastogenesis, RANK ligand, apoptosis, anticancer activity
MeSH terms
Bortezomib, Amino Acid Chloromethyl Ketones, Animals, Boronic Acids, Cell Differentiation, Cyclohexanones, Doxorubicin, Epoxy Compounds, Humans, Leukocytes, Mononuclear, Multiple Myeloma, Osteoclasts, Pyrazines, Transplantation, Heterologous, Signal Transduction, NF-kappa B, Apoptosis, Cell Line, Tumor, Mice, RANK Ligand

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