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


METHODS
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.
Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Claire
C
Fabre
Naoya
N
Mimura
Kathryn
K
Bobb
Sun-Young
SY
Kong
Güllü
G
Gorgun
Diana
D
Cirstea
Yiguo
Y
Hu
Jiro
J
Minami
Hiroto
H
Ohguchi
Jie
J
Zhang
Jeffrey
J
Meshulam
Ruben D
RD
Carrasco
Yu-Tzu
YT
Tai
Paul G
PG
Richardson
Teru
T
Hideshima
Kenneth C
KC
Anderson
D000590:Amino Acid Chloromethyl Ketones / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D003512:Cyclohexanones / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage; D004852:Epoxy Compounds / Q000008:administration & dosage*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014183:Transplantation, Heterologous
D000590:Amino Acid Chloromethyl Ketones; D001897:Boronic Acids; D003512:Cyclohexanones; D004852:Epoxy Compounds; D016328:NF-kappa B; C579556:PBS-1086; D011719:Pyrazines; D053245:RANK Ligand; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000069286:Bortezomib; D004317:Doxorubicin