Canonical nuclear factor kappaB pathway inhibition blocks myeloma cell growth and induces apoptosis in strong synergy with TRAIL.
OBJECTIVE
Intrinsic activation of nuclear factor kappaB (NF-kappaB) characterizes various hematologic malignancies. In this study, we specifically address the role of NF-kappaB blockade in mediated antimyeloma activity using the IkappaB kinase-2 pharmacologic inhibitor, AS602868.


METHODS
Human myeloma cell lines (n = 16) and primary myeloma cells (n = 10) were tested for their sensitivity to AS602868 in terms of proliferation and apoptosis. Both in vitro and in vivo experiments were conducted. Functional mechanisms regarding the apoptotic pathways triggered by AS602868 were studied. The potential proapoptotic synergy between AS602868 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was also evaluated.


RESULTS
Our results show that AS602868 efficiently targeted the canonical NF-kappaB pathway in myeloma cells and potently inhibited their growth in inducing apoptosis through Bax and caspase-3 activation. AS602868 also induced apoptosis in primary myeloma cells even in the presence of bone marrow mononuclear cells. Moreover, the IkappaB kinase-2 inhibitor targeted the paracrine effect on the bone marrow environment. Indeed, it decreased the intrinsic and myeloma-induced secretion of interleukin-6 from bone marrow stromal cells. In addition, AS602868 inhibited myeloma cell growth in the MM.1S xenograft myeloma model. Of particular interest, AS602868 strongly increased myeloma sensitivity to TRAIL in blocking TRAIL-induced NF-kappaB activation and in decreasing the expression of antiapoptotic proteins such as cFLIP and cIAP-1/2.


CONCLUSIONS
Taken together, our data point out the interest to inhibit the canonical NF-kappaB pathway in myeloma and clearly encourage clinical evaluation of novel therapies based on targeting NF-kappaB, especially in combination with TRAIL.
Romagnoli
Mathilde
M
INSERM, UMR 601, France.
Desplanques
Grégoire
G
Maïga
Sophie
S
Legouill
Steven
S
Dreano
Michel
M
Bataille
Régis
R
Barillé-Nion
Sophie
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011743:Pyrimidines / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C519899:AS602868; D000970:Antineoplastic Agents; D015850:Interleukin-6; D016328:NF-kappa B; D011743:Pyrimidines; D011971:Receptors, Immunologic; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051028:bcl-2-Associated X Protein; C098615:p50 natural killer cell receptor