Table 1 Various agents targeting the NF-κB pathway

Ibrutinib

Bruton’s tyrosine kinase (BTK) inhibitor

Canonical NF-κB pathway; BCR signaling

Yes—tested in vitro, in vivo, in clinical trials; approved by the FDA; 68% overall response rate in MCL patients [54]

Acalabrutinib

Second-generation Bruton’s tyrosine kinase (BTK) inhibitor

Canonical NF-κB pathway; BCR signaling

Yes—tested in relapsed or refractory mantle cell lymphoma in a single-arm, multicenter, phase 2 trial; 81% overall response and 40% complete response for 124 patients at a median follow-up of 15.2 months [55]

Bortezomib

Proteasome inhibitor → prevents degradation of ubiquitinated IκB; induces cell death via oxidative and ER stress → NOXA upregulation (NF-κB independent)

Canonical NF-κB pathway

Yes—tested in vitro, in vivo, and in clinical trials; approved by the FDA; 33% overall response rate in R/R MCL patients [56]

Rituximab

Chimeric anti-CD20 antibody; downregulates Bcl-x(L) expression; decreases the phosphorylation of NF-κB-inducing kinase, IκB kinase, and IκBα; diminishes IKK kinase activity; and decreases NF-κB DNA-binding activity

Canonical and non-canonical NF-κB pathways

Yes—widely used in clinical treatment of patients with non-Hodgkin lymphoma (NHL); also tested in vitro in CD20(+) drug-resistant cell lines Ramos (Bcl-2(−)/Bcl-x(L)(+)) and Daudi (Bcl-2(+)/Bcl-x(L)(+)) [57]

Lenalidomide

Downregulates pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6

Canonical NF-κB pathway

Yes—approved for the treatment of patients with MCL whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib

Idelalisib

PI3Kδ inhibitor

Cross-talk between NF-κB and PI3K/Akt pathways

Yes—phase I study in 2014 for treatment of relapsed/refractory MCL patients, overall response rate of 40% (16/40 patients) [58]; phase I study in 2014 for treatment of patients with indolent non-Hodgkin lymphoma (NHL), overall response rate of 47% (30/64 patients) [44]

Auranofin

Inhibits homodimerization of toll-like receptor 4 (TLR4), thereby suppressing TLR-mediated activation of NF-κB [59]

Canonical NF-κB pathway; TLR signaling

Phase I/II clinical trial at University of Kansas Medical Center to evaluate safety and efficacy of auranofin in chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and/or prolymphocytic lymphoma (PLL) patients (clinicaltrials.gov)

Duvelisib

PI3K inhibitor

Cross-talk between NF-κB and PI3K/Akt pathways

Yes—tested in vitro and in patient-derived xenograft studies; inhibited MCL growth in vitro and in PDX mice [45]

ACP-319

PI3K inhibitor

Cross-talk between NF-κB and PI3K/Akt pathways

Yes—undergoing phase 1/2 clinical trial in combination with ACP-196 in subjects with B cell malignancies, including MCL (no study results posted yet—clinicaltrials.gov)

AM-0216 and AM-0561

NIK inhibitors

Non-canonical NF-κB pathway

Tested in vitro in multiple myeloma cells; was not possible to do in vivo studies due to poor pharmacokinetic properties, but drug combination may be more promising [35]

ASN002

Syk/jak inhibitor

Canonical NF-κB pathway; BCR signaling

Showed anti-proliferative activity in many cell lines and inhibited tumor growth in a multiple myeloma xenograft model; phase I/II ongoing clinical study [60]

CUDC-907

PI3K/histone deacetylase (HDAC) inhibitor

Canonical NF-κB pathway; BCR and TCR signaling

Yes—inhibits tumor growth of ibrutinib-resistant MCL in vitro and in PDX model [61]; phase I/II trial for relapsed or refractory lymphoma or multiple myeloma (clinicaltrials.gov)

Emetine

IκBα phosphorylation inhibitor

Canonical NF-κB pathway

Tested in vitro and in vivo in diffuse large B cell lymphoma cells; induced cell death and demonstrated significant inhibition of tumor growth [62]

Lestaurtinib

IκBα phosphorylation inhibitor

Canonical NF-κB pathway

Showed biological and clinical activity in phase 1/2 trial for patients with relapsed or refractory acute myeloid leukemia [63]

Mesalamine

Blocks p65-dependent transactivation

Canonical NF-κB pathway

Not tested in MCL cells; first line agent for treating ulcerative colitis; maintains remission in mild to moderate UC [64]

Fenofibrate

Inhibits the TNF-α/NF-κB axis to induce apoptosis; modulates the expression of anti-apoptotic genes associated with MCL; decreases DNA binding of NF-κB

Canonical NF-κB pathway, cross-talk with TNF signaling

Tested in vitro—decreases growth of Mino, SP53, and Jeko-1 cell lines; induces apoptosis in MCL cell lines Mino and Jeko-1 in vitro; decreases cyclin D1 expression in Mino and SP53 [65]